Formulation comprising particles

ABSTRACT

The invention provides ingestible particles comprising a water-swellable or water-soluble polymeric component, a lipid component, and optionally an amino acid, a vitamin and/or a micro-nutrient. The polymeric component may be embedded in the lipid component. The particle may further comprise an inert core and/or an outer layer which rapidly disintegrates after oral ingestion. The invention further provides methods for preparing the ingestible particles and uses thereof.

FIELD

The present invention relates to oral compositions for the delivery ofbioactive agents to the gastrointestinal tract.

BACKGROUND

In the field of oral drug delivery it is of interest to developgastroretentive dosage forms for bioactive substances. Substancesassociated with bioactivity are typically synthetic compounds, so calledsmall molecules. Often such synthetic compounds require a slow releasefrom their dosage form after oral administration to minimise sideeffects and maximise efficacy. For this purpose drug substances may beincorporated in a matrix comprising lipids. Due to the hydrophobicnature of the lipidic components of such a formulation, a lipophilic oramphiphilic bioactive substance may be released more slowly into thegastrointestinal lumen as compared to a standard tablet matrixcomprising highly water-soluble excipients. Due to the fact that therelease from a sustained release matrix may proceed over the course ofup to six or eight hours but the typical time of gastric emptying islimited to only two hours, there is a need for engineeringgastroretentive properties into such a slow release formulation in orderto maximise the effective time of drug delivery. Gastroretention may beachieved by rendering the formulation mucoadhesive. A gastricmucoadhesive system will bind to the mucosa of the gastric wall andprolong the residence time of the system, providing for a more extendedrelease period. The combination of mucoadhesive properties andslow-release lipid matrix has been addressed. US 2006/0134144 detailsmucoadhesive compositions for solubilisation of insoluble drugs. Here,pharmaceutical compounds are formulated with monoglycerides and oil. WO03/037355 to Reckitt Benckiser Healthcare mentions polyacrylatecompositions for use in protecting mucosa. In addition to themucoadhesive polymer, such compositions comprise Vitamins and oil. EP0580861 to Nippon Shinyaku Company claims a sustained release capsulefor adhesion in the gastrointestinal tract. Hard capsules were filledwith drug substance, adhesion polymer and filler polymers and liquidparaffin. U.S. Pat. No. 5,571,533 to Recordati disclosescontrolled-release mucoadhesive compositions for the oral administrationof drug substance furosemide. In this patent, furosemide-lipid granuleswere coated with mucoadhesive polymers. U.S. Pat. No. 6,368,635 toTakeda Chemical Industries describes gastrointestinal mucosa-adherentmatrices. High-melting triglyceride was mixed with drug substance andacryl acid polymer, and solid dosage forms were prepared withmucoadhesive properties. From recent research in the area ofanti-obesity, it has emerged that triglycerides or their digestivedegradation products, free fatty acids, may act as bioactive substancesin their own right. For instance, it is well documented that theinfusion of lauric acid or oleic acid into the duodenum by means of afeeding tube provides for strong satiety signalling. Consequently, thereis a need to provide sustained release formulations of free fatty acids.

WO 2011/136975 A1 describes a method and system for displaying gastricband information, and more specifically gastric band information whichcan support adjustment of a gastric band. The adjustment of the gastricband may be dependent on several pieces of data. Such data may includesatiety state date.

Alternative non-invasive approaches for the treatment of obesity mayinfer satiety or the feeling of fullness or satisfaction through avariety of different ingestible compositions such as gelling systems orcertain nutrient compositions.

Whereas for gastric banding, satiety state information may be ofrelevance to the healthcare professional to monitor efficacy of thedevice, for non-invasive satiety compositions it may be useful tocollect and display satiety state information in order to supportadministration of the satiety-inducing composition and to increasecompliance.

Such satiety-state information are conventionally collected as handwritten documents, or typed data entry into computer spreadsheets orforms. More preferably, such satiety-state data may be collected inreal-time by means of a software application running on a computer or amobile device such as a smartphone or a wearable device.

It is an object of the present invention to provide an effective methodfor delivering fatty acids and lipids based on fatty acids to thegastrointestinal tract. A further object is to provide means for thedelivering such fatty acids and lipids to specific regions within thegastrointestinal tract, such as the stomach or the duodenum. A furtherobject is to provide compositions, dosage forms and/or formulationswhich are useful for the oral delivery of fatty acids and lipids basedon fatty acids. A yet further object is to provide a treatment forobesity which encourages adherence to the therapy and motivates thepatient to comply with a prescribed administration regimen.

Further objects will become apparent on the basis of the followingdescription including the examples, and the patent claims.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides an ingestible particle havinga sieve diameter in the range from 0.05 to 3 mm, comprising awater-swellable or water-soluble polymeric component, a first lipidcomponent, and optionally an amino acid, a vitamin and/or amicro-nutrient. The first lipid component comprises a medium or longchain fatty acid compound. The particle is further characterised in thatthe water-swellable or water-soluble polymeric component is embeddedwithin, and/or coated with, the lipid component.

The first lipid component in/by which the water-swellable orwater-soluble polymeric component is embedded or coated may representthe active core of the ingestible particle. The particle may further becoated with a coating layer that comprises a second lipid componentand/or a hydrophilic component. Optionally, the coating layer issubstantially free of the water-swellable or water-soluble polymericcomponent.

Alternatively, the ingestible particle may comprise an inert core, e.g.composed of an inert material, and the first lipid component in/by whichthe water-swellable or water-soluble polymeric component is embedded orcoated may be designed as a coating covering the inert core. Moreover,the particle may further comprise a second coating layer covering thefirst coating. The second coating comprises a second lipid componentand/or a hydrophilic component. Optionally, the second coating layer issubstantially free of the water-swellable or water-soluble polymericcomponent.

Preferably, the first lipid component comprises at least one medium orlong chain fatty acid compound with a melting range below 37° C., eitherper se or in the hydrated state.

In a further aspect, the invention provides compositions for oraladministration which comprise the ingestible particles or which areprepared from them, such as bottles, sachets, stick packs, capsules ortablets or other dosage units.

In a yet further aspect, the invention provides the use of the particlesand of the compositions based on the particles for the prevention and/ortreatment of obesity, or a disease or condition associated with obesity.Moreover, the use in appetite suppression, induction of satiety and/orbody weight reduction is provided.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the invention provides an ingestible particle havinga sieve diameter in the range from 0.05 to 3 mm, comprising awater-swellable or water-soluble polymeric component, a first lipidcomponent, and optionally an amino acid, a vitamin and/or amicro-nutrient. The first lipid component comprises a medium or longchain fatty acid compound. The particle is further characterised in thatthe water-swellable or water-soluble polymeric component is embeddedwithin, and/or coated with, the lipid component.

For the avoidance of doubt, it should be understood that the presence ofthe amino acid, the vitamin and/or the micro-nutrient in the particlesaccording to the invention (and/or mixtures for the preparation of saidparticles) is optional in all embodiments, unless where explicitlystated otherwise. This means that, as used herein, listings includingthe amino acid, the vitamin and/or the micro-nutrient simply refer tothe specific embodiments in which the optional amino acids, vitaminsand/or micro-nutrients are present, while not excluding thoseembodiments without these optional components.

Further, the incorporation of the amino acid, the vitamin and/or themicro-nutrient into the particles of the invention are independent ofeach other; i.e. the particles may be free of all these components,comprise only one, two or three of the four, or they may comprise allfour of them.

It should also be understood that, as used herein, the terms ‘a’ or ‘an’or ‘the’ or features described in their singular form do not exclude aplurality of the respective features. Unless explicitly stated ordescribed otherwise, expressions such as “an amino acid”, “a vitamin”,“the micro-nutrient”, “the polymer” or the like are chosen solely forreasons of simplicity and are meant to encompass one or more aminoacid(s), vitamin(s), micro-nutrient(s), polymer(s) etc.; e.g. in theform of blends, or mixtures, of two or more of the respectivecomponents.

The inventors have found that the ingestible particles as definedherein, and in particular oral compositions comprising or prepared froma plurality of the particles, are capable of effectively inducingsatiety, of suppressing the appetite, and thereby may be used to preventor treat obesity or conditions associated with obesity; e.g. by usingthe ingestible particles as defined herein and/or compositionscomprising or prepared from a plurality of these particles for bodyweight reduction. Without wishing to be bound by theory, it is currentlybelieved that upon oral administration, the fatty acid or fatty acidester comprised in the particle is more effectively delivered to themucosa of the gastrointestinal tract, such as the stomach or duodenum,by virtue of the water-swellable or water-soluble polymeric component,which may be instrumental in providing a prolonged or otherwiseincreased interaction of the fatty acid material with target structuresin the mucosa. Furthermore, the water-swellable or water-solublepolymeric component may be instrumental in providing a prolonged orotherwise increased interaction of the amino acid, the vitamin and/orthe micro-nutrient (if present) with target structures in the mucosa.

Possibly, the water-swellable or water-soluble polymeric componentprolongs the integrity of the particle after ingestion as compared to alipid particle without the water-swellable or water-soluble polymericcomponent. Prolonged integrity of the lipid-containing particle mayresult in more rapid gastric emptying of the particles and thereforemore rapid interaction of particle-derived fatty acids or fatty acidesters with the intestinal mucosa. Prolonged integrity of thelipid-containing particle may also result in the delivery of fatty acidsor fatty-acid esters to the more distal parts of the small intestinesuch as the jejunum or ileum.

Possibly, the water-swellable or water-soluble polymer componentincreases the digestibility of a lipid component of otherwise limiteddigestibility such as a hard fat such as for instance tristearin. In apublished rat feeding study, tristearin (Dynasan® 118, melting range72-75° C.) was found to provide an energy content of only 3 kcal/g,corresponding to a true digestibility of stearic acid from tristearin ofonly 0.15 g/g independent from intake. Possibly, the water-swellable orwater-soluble polymer component enhances the particle's surface wettingproperties and/or facilitates water and bile acid access and subsequentemulsification and lipase-mediated hydrolysis of the lipid.

Possibly, the water-swellable or water-soluble polymeric componentprovides the particle with mucoadhesive properties, in particular incombination with a prolonged integrity of the particle.

As used herein, an ingestible particle is a particle which is inprinciple suitable for oral ingestion, or oral administration. Aparticle which by virtue of its composition, size and morphology wouldbe suitable as a food component or a component of a pharmaceuticalcomposition for oral use is an example of an ingestible particle.

The particle has a sieve diameter in the range from about 0.05 mm toabout 3 mm, which means that it would normally pass through a sievehaving an aperture or opening size of about 3 mm, but not through asieve having an aperture or opening size of about 0.05 mm or less. Theparticle may also have a diameter in the range from about 0.1 mm toabout 2.5 mm, or from about 0.1 mm to about 2 mm, such as about0.25±0.20 mm, about 0.5±0.25 mm, about 1.0±0.25 mm, about 1.5±0.25 mm,or about 2.0±0.25 mm, respectively. Within a composition comprising aplurality of particles according to the invention, these particle sizesshould be interpreted to characterise the preferred mass median sievediameters of the ingestible particles.

The water-swellable or water-soluble polymeric component is ahydrophilic or amphiphilic polymeric material capable of dissolving orswelling in an aqueous environment. The material may comprise amucoadhesive compound or mixture of mucoadhesive compounds, or it may becapable of inducing mucoadhesiveness to the particle. If it is amixture, it may also comprise one or more constituents which arethemselves not water-swellable or mucoadhesive, as long as the mixtureis water-swellable.

As used herein, swelling by water, or in an aqueous environment,typically means the volume increase of a solid body caused by an influx,or diffusion process of water accompanied by hydration, i.e. wetting andabsorption of moisture.

The water-soluble polymeric component is a hydrophilic or amphiphilicpolymer of a solubility in water of at least 1 mg/L.

Prolongation of particle integrity is the prolongation of time duringincubation under in vivo or simulated in vivo conditions in which themajority (more than 50%) of particles do not decrease their volume ormass or melt into droplets. Particle integrity may be readily inferredby visual inspection by the naked eye or by means of a microscope orthrough imaging technology, including microscopic imaging, andsubsequent computer-aided image processing.

Mucoadhesiveness is the capability of adhering to a mucosa, or mucosalmembrane. Various conventional methods are available to determinemucoadhesiveness, such as tensile strength measurements, ellipsometry,or rheological measurements (D. Ivarsson et al., Colloids Surf BBiointerfaces, vol. 92, pages 353-359, 2012). Even though these methodsmay not provide absolute values for mucoadhesiveness as such, theyindicate the presence and relative magnitude of mucoadhesiveness of amaterial.

To determine mucoadhesiveness in the context of the invention, it ispreferred that a modified falling liquid film method (described amongother method in Mucoadhesive drug delivery systems, Carvalho F. C. etal., Brazilian Journal of Pharmaceutical Sciences 46 (2010)) isemployed. According to the method, the selected mucous membrane (e.g.from pig stomach) is placed in a petri dish together with simulatedgastric fluid at a controlled temperature of 37° C. The petri dish isplaced on a table undergoing a tilting movement. Both tilting movementand volume of buffer are selected so that small waves of buffercontinuously run over the surface of the mucous tissue. In the fallingliquid film method, a similar agitation is achieved by pumping bufferover mucosal tissue tilted at a 45° angle. The amount of particlesremaining on the mucous membrane after a specified time interval can bequantified by various methods. For instance, particles can be counted,optionally using a magnifying glass or microscope, or they may becollected, dried and measured gravimetrically.

In the context of the invention, the water-swellable or water-solublepolymeric component may have, or induce, sufficient mucoadhesivestrength to cause attachment to a mucosal membrane upon contact with,and to cause the particle or a component thereof to stay attached for aperiod of time which is significantly longer than a material which isnot mucoadhesive, such as a solid triglyceride or a lipophilic polymer,e.g. polytetrafluoroethylene. In one preferred embodiment, thewater-swellable or water-soluble polymeric component comprises amucoadhesive polymer. In particular, it may comprise at least onepolymeric material selected from poly(carboxylates), chitosan, celluloseethers, and xanthan gum.

In a further preferred embodiment, the water-swellable or water-solublepolymeric component is a plant fibre. In the context of the invention, aplant fibre includes selected individual components of plant fibres orderived therefrom, as well as their mixtures. For example, a suitablewater-swellable or water-soluble polymeric component is psyllium seedhusk, or psyllium seed husk fibres, also referred to as psyllium husk orsimply psyllium. Psyllium seed husk are the seed coats of the seeds ofPlantago ovata, also known as Desert Indianwheat or Blond Psyllium. Amajor component of psyllium seed husk is soluble but indigestiblepolysaccharide fibers which are highly swellable in water. Psyllium isknown as a source of dietary fibre and as a mild laxative or stoolsoftener.

If a poly(carboxylate) is used, this is preferably selected frompoly(acrylic acid), poly(methacrylic acid), copolymers of acrylic andmethacrylic acid, and poly(hydroxyethyl methacrylic acid), or fromalginic acid or pectin or carboxymethylcellulose. The cellulose ether ispreferably selected from hydroxyethyl cellulose, hydroxypropyl cellulose(also known as hyprolose), hydroxypropyl methylcellulose (also known ashypromellose), and methylcellulose. If an ionic polymer is used such asa poly(carboxylate) and/or a carboxymethylcellulose, this may bepartially or entirely neutralised, preferably as sodium or potassiumsalt, most preferably as the sodium salt. Moreover, the polymericmaterial may be at least partially crosslinked.

In a further preferred embodiment, the mucoadhesive polymer is acopolymer of acrylic acid and methacrylic acid, or of acrylic ormethacrylic acid and maleic acid. The copolymer may be crosslinked withsmall amounts of a polyalkenyl polyether. Such copolymers are highlyhydrophilic and capable of absorbing large amounts of water which causestheir swelling.

Particularly suitable for carrying out the invention are, for example,carbomers. Carbomer resins are high molecular weight, crosslinkedacrylic acid-based polymers. Commercial versions of carbomers are soldas e.g. Carbopol®, Noveon®, Pemulen®, Polygel®, Synthalen®, Acritamer®or Tego Carbomer®. Most of these brands include various carbomer grades.

For example, the Carbopol® polymer series encompasses homopolymers,copolymers, interpolymers as exemplified by Carbopol® Aqua SF-1(acrylate copolymer, a lightly cross-linked acrylate copolymer),Carbopol® Aqua SF-2 (acrylate crosspolymer-4), Carbopol® Aqua CC(polyacrylate-1 crosspolymer), Carbopol® 934 (carbomer, acrylatehomopolymer cross-linked with allyl ethers of sucrose), Carbopol® 940(carbomer), Carbopol® 941 (carbomer), Carbopol® 971P (carbomer, lightlycrosslinked with allyl pentaerythritol), Carbopol® 71G (a free-flowinggranular form of Carbopol® 971P for use in direct compressionformulations), Carbopol® 974P (carbomer, highly crosslinked), Carbopol®980 (carbomer), Carbopol® 980 (carbomer), Carbopol® 981 (carbomer, allylpentaerythritol crosslinked), Carbopol® 1342 (acrylates/C 10-30 alkylacrylate crosspolymer, copolymer of acrylic acid and C10-C30 alkylacrylate crosslinked with allyl pentaerythritol), Carbopol® 1382(acrylates/C10-30 alkyl acrylate crosspolymer, copolymer of acrylic acidand C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol),Carbopol® 2984 (carbomer), Carbopol® 5984 (carbomer), Carbopol® Ultrez10 (carbomer), Carbopol® Ultrez 20 (acrylates/C10-30 alkyl acrylatecrosspolymer), Carbopol® Ultrez 21 (acrylates/C10-30 alkyl acrylatecrosspolymer), Carbopol® Ultrez 30 (carbomer), Carbopol® ETD 2001,Carbopol® ETD 2020 (acrylates/C10-30 alkyl acrylate crosspolymer,interpolymer containing a block copolymer of polyethylene glycol and along chain alkyl acid ester), Carbopol® ETD 2050 (carbomer).

Polymer grades approved for pharmaceutical use are preferred amongthese, such as those which comply with a pharmacopoeial monograph, suchas the monograph “Carbomer” of the European Pharmacopoeia (Ph. Eur. 8)or the monographs in the US Pharmacopoeia/National Formulary (USP-NF)with the titles, “Carbomer 910”, “Carbomer 934”, “Carbomer 934P”,“Carbomer 940”, “Carbomer 941”, “Carbomer Homopolymer”, “CarbomerCopolymer”, “Carbomer Interpolymer”, or “Carbomer 1342”.

Also particularly suitable are polycarbophils (USP-NF), which representhigh molecular weight acrylic acid polymers crosslinked with divinylglycol. They provide excellent bioadhesive properties. An example of apreferred grade of polycarbophil is NOVEON® AA-1.

Optionally, the water-swellable polymeric or water-soluble componentcomprises at least one polysaccharide approved for oral use as excipientor food additive or food ingredient. The at least one polysaccharide maybe selected from the groups of cationic polysaccharides, anionicpolysaccharides and non-ionic polysaccharides.

Suitable cationic polysaccharides include, but are not limited to,chitosan, polysaccharides modified by means of quaternary ammoniumgroups (for example cationic guar gum, cationic cellulose, cationichydroxyethyl cellulose, and cationic starch), derivatives thereof, ormixtures of two or more thereof.

Alternatively, the cationic polysaccharide is a polymeric material withbasic amino groups which are at least partially protonated in a neutralenvironment. The cationic polysaccharide may be provided or incorporatedas a free base, as a quantitatively protonated salt form, or any mixtureof the two forms.

The “free base” form refers to a polymer such as polyglucosamine(chitosan) comprising amino side chains in the base form, e.g. —NH₂. The“salt form” refers to a polymer such as polyglucosamine (chitosan)comprising amino side chains in the salt form, e.g. —NH₃+Cl⁻ forchloride salts of ammonium groups. It is understood that the salt formmay refer to mixtures of salts, e.g. the salt form may be composed ofmixtures of different salts such as —NH₃+Cl⁻ and —NH₃+CH₃—COO⁻. “Anymixture of the two forms” refers to a polymeric material comprisingamino groups, where a fraction of the amino groups is present in thefree base form, e.g. as —NH₂ for primary amino groups, and a fraction ofthose side chains is present in the salt form, e.g. —NH₃+Cl⁻. Forinstance, such a mixture may be referred to as partial chloride salt ofchitosan.

“Chitosan” for the purpose of the invention is defined as chitosanderived from fungi or derived by deacetylation of chitin, wherein theaverage degree of deacetylation is preferably more than about 75%, morethan about 80%, more than about 90%, or more than about 95%,respectively. The degree of deacetylation refers to the percentage ofthe chitin's amino groups that are deacetylated. A particularlypreferred chitosan is derived from fungal biomass selected from thegroup consisting of Candida Guillermondii, Aspergillus niger,Aspergillus terreus, and combinations thereof, the chitosan containingmaterial having greater than 85 percent deacetylation of N-acetyl groupsin the chitin and exhibiting a viscosity of less than 25 centipoise(mPa·s) at 25° C. in 1 percent aqueous acetic acid.

Suitable anionic polysaccharides include, but are not limited to,sulphated glycosamino glycans including heparans, heparansulfates,heparins; alginates; propylene glycol alginates; carrageenans; cellulosesulfate; carboxymethyl cellulose; fucoidan; galactans containingglucuronic acid or galacturonic acid; chondroitins or chondroitinsulphates; gellan gums; hyaluronans and hyaluronic acids; modifiedstarches such as octenyl succinate starches or monostarch phosphates,oxidised starches or carboxymethylated starches; pectic acids, pectinsincluding amidated pectins, homogalacturonans, substitutedgalacturonans, rhamnogalacturonans, their methyl and ethyl esters;porphyrans; sulphated galactanes; tragacanth or gum karaya; xanthan gumsand xylans.

One particularly suitable polycarboxylate polysaccharide is alginicacid. Alginic acid is a linear copolymer with homopolymeric blocks of(1-4)-linked β-D-mannuronate (M) and its C-5 epimer α-L-guluronate (G)residues, respectively, covalently linked together in differentsequences or blocks. The monomers can appear in homopolymeric blocks ofconsecutive G-residues (G-blocks), consecutive M-residues (M-blocks) oralternating M and G-residues (MG-blocks).

The anionic polysaccharide may be incorporated in the form of a freeacid, or as the neutralised salt form of the acid, or as a mixture ofthese, i.e. as a partially neutralised salt. The “free acid” form refersto a polymeric material comprising acid groups in the non-ionised,protonated acid form, e.g. —COOH or —SO₄H₂. The “salt form” refers to apolymeric material with acid groups in the ionised form, or salt form,e.g. —COO⁻ Na⁺ for sodium salts of carboxylates or —SO₄ ²⁻2 Na⁺ forsodium salts of sulphates. It is understood that the salt form may referto mixtures of salts, e.g. the salt form may be composed of mixtures of—COO⁻ Na⁺ and —COO⁻ K+ or —COO—Ca²⁺—COO⁻ salts. “Any mixture of the twoforms” refers to a polymeric material comprising acid groups, where afraction of those groups is present in the non-ionised acid form, e.g.as —COOH for carboxylic acids, and another fraction of the acid groupsis present in the ionised salt form, e.g. —COO⁻ Na⁺ for sodium salts ofcarboxylic acids. For instance, such a mixture may be referred to aspartial sodium salt of alginic acid.

Preferably, the anionic polysaccharide is an anionic dietary fibre.Dietary fibres, for the purpose of the invention, are carbohydratepolymers with ten or more monomeric units which are not hydrolysable byendogenous enzymes in the small intestine of humans. They typicallyrepresent carbohydrate polymers which have been obtained from food rawmaterial by physical, enzymatic or chemical means, or syntheticcarbohydrate polymers.

Preferably, the anionic polysaccharide is alginic acid,carboxymethylcellulose, hyaluronan, sodium alginate, propylene glycolalginate, carrageenan, gellan gum, pectin, tragacanth or xanthan gum.Particularly preferred is that the at least one anionic polysaccharideis carboxymethylcellulose, sodium alginate or propylene glycol alginate,pectin, xanthan gum, or hyaluronan. Optionally, a combination of anionicpolysaccharides is employed, such as sodium alginate and xanthan, orsodium alginate and pectin.

Pectic polysaccharides (pectins) are rich in galacturonic acid. Severaldistinct polysaccharides have been identified and characterised withinthe pectic group. Homogalacturonans are linear chains of α-(1-4)-linkedD-galacturonic acid. Substituted galacturonans are characterised by thepresence of saccharide appendant residues (such as D-xylose or D-apiosein the respective cases of xylogalacturonan and apiogalacturonan)branching from a backbone of D-galacturonic acid residues.Rhamnogalacturonan I pectins (RG-I) contain a backbone of the repeatingdisaccharide: 4)-α-D-galacturonic acid-(1,2)-α-L-rhamnose-(1). From manyof the rhamnose residues, sidechains of various neutral sugars maybranch off. The neutral sugars are mainly D-galactose, L-arabinose andD-xylose, with the types and proportions of neutral sugars varying withthe origin of pectin. Another structural type of pectin isrhamnogalacturonan II (RG-II). Isolated pectin has a molecular weight oftypically 60-130,000 g/mol, varying with origin and extractionconditions. In nature, around 80 percent of carboxyl groups ofgalacturonic acid are esterified with methanol. This proportion isdecreased to a varying degree during pectin extraction. The ratio ofesterified to non-esterified galacturonic acid determines the behaviourof pectin in food applications. This is why pectins are classified ashigh- vs. low-ester pectins (short HM vs. LM-pectins), with more or lessthan half of all the galacturonic acid esterified. The non-esterifiedgalacturonic acid units can be either free acids (carboxyl groups) orsalts with sodium, potassium, or calcium. The salts of partiallyesterified pectins are called pectinates; if the degree ofesterification is below 5 percent the salts are called pectates; theinsoluble acid form pectic acid. Amidated pectin is a modified form ofpectin. Here, some of the galacturonic acid is converted with ammonia tocarboxylic acid amide. Most preferred pectins are high ester pectins.

Suitable non-ionic polysaccharides include, but are not limited to,agaroses; amylopectins; amyloses; arabinoxylans; beta glucans includingcallose, curdlan, chrysolaminarin or leucosin, laminarin, lentinan,lichenin, pleuran, schizophyllan, zymosan; capsulans; cellulosesincluding hemicelluloses, cellulose esters such as cellulose acetate,cellulose triacetate, cellulose propionate, cellulose acetate propionateand cellulose acetate butyrate; cellulose ethers such asmethylcellulose, hydroxyethyl methylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxyethyl cellulose, hydroxypropylcellulose (hyprolose), hydroxyethyl hydroxypropyl cellulose, methylethyl cellulose or alkoxy hydroxyethyl hydroxypropyl cellulose, whereinthe alkoxy group is unbranched or branched and comprises 2 to 8 carbonatoms; chitins; cyclodextrins; dextrans; dextrins (for examplecommercially available as Nutriose® or Benefiber®); galactoglucomannans;galactomannans including fenugreek gum, guar gum, tara gum, locust beangum or carob gum; glucomannans including konjac gum; fructans includinginulin, levan, sinistrin or phlein; maltodextrins; glycogens; pullulans;starches including resistant starches, modified starches such asacetylated starch, hydroxypropylated starch or hydroxyethyl starch;polydextroses; welan gum and xyloglycans.

Preferably, the non-ionic polysaccharide is a non-ionic dietary fibre.Preferably, the non-ionic polysaccharide is selected from the groupconsisting of beta glucans, cellulose ethers, guar gums, galactomannans,glucomannans, inulins and dextrins. Preferably, the non-ionicpolysaccharide is hydroxypropyl methylcellulose (hypromellose) or locustbean gum, or oat or barley beta glucan or konjac gum or resistantdextrin. Among the particularly preferred non-ionic polysaccharides arehydroxypropyl methylcellulose (hypromellose), hydroxypropylcellulose,beta glucan from oat or barley and resistant dextrin from starch.

Resistant dextrins are short chain glucose polymers without sweet tastewhich are relatively resistant to the hydrolytic action of humandigestive enzymes. They can be made for instance from wheat (NUTRIOSE®FB range or Benefiber®) or maize starch (NUTRIOSE® FM range), using ahighly controlled process of dextrinisation followed by achromatographic fractionation step. During the dextrinisation step, thestarch undergoes a degree of hydrolysis followed by repolymerisationthat converts it into fibre: in addition to the typical starch α-1,4 andα-1,6 digestible linkages, non-digestible glycosidic bonds such as β-1,2or β-1,3, are formed, which cannot be cleaved by enzymes in thedigestive tract.

Optionally, the water-swellable or water-soluble polymeric componentaccording to the invention comprises more than one polysaccharide.Preferred is in particular the selection of an anionic polysaccharideand a non-ionic polysaccharide, especially the combination of xanthangum and hydroxypropyl methylcellulose (hypromellose).

Optionally, the water-swellable or water-soluble polymeric componentaccording to the invention comprises a synthetic water swellable orwater-soluble polymeric material such as polyvinyl alcohol, polyvinylacetate, polyethylene glycols (PEG), polypropylene glycols (PPG) orpolyvinylpyrrolidones (PVP). Such polymer may be linear, branched orcrosslinked, as for instance in crospovidone (crosslinkedpolyvinylpyrrolidone), or a PEG hydrogel.

Optionally, the water-swellable or water-soluble polymeric componentcomprises a thiolated polymer such as chitosan-4-thiobutylamidine, achitosan-thioglycolic acid conjugate, a chitosan-cysteine conjugate, achitosan glutathione conjugate, a polycarbophil-cysteine conjugate, apolyacrylic acid-cysteine conjugate, a carboxymethyl cellulose-cysteineconjugate, or any mixture or combination of two or more of these.

The first lipid component comprises a medium or long chain fatty acidcompound. A fatty acid compound, as used herein, may refer to a freefatty acid, a partially or completely neutralised fatty acid, i.e. thesalt of a fatty acid, such as a sodium, potassium or calcium salt, or anesterified fatty acid. An esterified fatty acid may have, as alcoholresidue, a glycerol, so that the esterified fatty acid is a mono-, di-or triglyceride. The acyl chain of the fatty acid may be saturated orunsaturated.

A medium chain fatty acid is understood as fatty acid with an acylresidue of 6 to 12 carbon atoms, whereas a long chain fatty acid means afatty acid with an acyl chain of 13 to 21 carbon atoms. Among thepreferred medium chain fatty acids are caprylic acid, capric acid, andlauric acid, including their esters and salts, in particular theirmono-, di- and triglycerides and their sodium, potassium and calciumsalts. In the case of di- and triglycerides, these may also havedifferent fatty acid residues per glyceride molecule. Examples ofpreferred long chain fatty acids include myristic acid, palmitic acid,stearic acid, arachidic acid, behenic acid, myristoleic acid,palmitoleic acid, sapienic acid, oleic acid, linoleic acid, andlinolenic acid, and the respective salts and glycerides.

In one of the preferred embodiments, the first lipid component comprisesone or more partial glycerides of a medium or long chain fatty acid, inparticular monoglycerides of a medium or long chain fatty acid. Forexample, monoolein or monolaurin are very suitable for carrying out theinvention, individually or in combination with each other. As usedherein, a monoglyceride such as monoolein or monolaurin may beincorporated as a substantially pure compound or as a mixture of mono-and diglycerides or even mono-, di- and triglycerides with various fattyacids, but with a high content (“enriched”) of a particularmonoglyceride compound. For example, a monoolein grade may be used whichcomprises at least about 40% (or at least about 50%, or 60% or 70% or80% or 90%) of the actual monoglyceride of oleic acid.

The first lipid component may of course represent a mixtureincorporating two or more fatty acids, and/or fatty acid esters orsalts. For example, the component may comprise one or more a fattyacids, which may be partially or completely neutralised, in combinationwith one or more glycerides, such as triglycerides.

The constituent(s) of the first lipid component may represent a native,synthetic or semisynthetic material. For example, cocoa butter may beused, which is itself a mixture of various lipid compounds, most ofwhich represent fatty acid compounds as defined herein. Anotherpreferred constituent of the first lipid component is palm stearin orpalm kernel stearin. Palm stearin is the solid fraction of palm oil thatis produced by partial crystallization at controlled temperature.

In one embodiment, the first lipid component comprises one or more freefatty acids. For example free oleic acid or lauric acid may be part ofthe lipid component. Other preferred free fatty acids are mixtures ofunsaturated fatty acids such as the so-called omega fatty acids orconjugated linoleic acids. Conjugated linoleic acids (CLA) are a familyof isomers of linoleic acid. Conjugated linoleic acid is both a transfatty acid and a cis fatty acid as the double bonds of CLAs areconjugated and separated by a single bond between them. Brands of CLAsare marketed as dietary supplements (Tonalin®, BASF, and Clarinol®,Stepan). Omega-3 fatty acids are polyunsaturated fatty acids (PUFAs)with a double bond (C═C) at the third carbon atom from the end of thecarbon chain. Examples of omega-3 fatty acids are α-linolenic acid (ALA)(found in plant oils), eicosapentaenoic acid (EPA), and docosahexaenoicacid (DHA) (both commonly found in marine oils). If the first lipidcomponent comprises an unsaturated fatty acid, it may also comprise anantioxidant such as vitamin E or a derivative thereof.

In one of the preferred embodiments, the medium or long chain fatty acidcompound in the first lipid component, either per se in vitro or in thehydrated state in vivo, has a melting range of below 37° C. As usedherein, the melting range is understood as being below 37° C. if thelower (but not necessarily the upper) limit of the range is below 37° C.In other words, a compound having a melting range of 35° C. to 38° C. isan example of a material with a melting range of below 37° C. accordingto the invention. In other words, at least some of the fatty acidmaterial in the lipid component should melt at the physiologicaltemperature of the human body according to this embodiment. Moreover,the specified melting range is also met if the lipid component iscapable of hydration, wherein the melting range in the hydrated state isbelow 37° C. Such behaviour of some lipids has also been described as“melting by hydration”.

According to a further preference, the first lipid component comprises amedium or long chain fatty acid compound having a melting range, orlower limit of the melting range, between about 10° C. and 37° C., orbetween about 25° C. and 37° C., respectively.

It has been surprisingly found by the inventors that particlescontaining the water-swellable or water-soluble polymeric componentembedded in, or coated with, a lipid component comprising suchlow-melting fatty acid compound(s) are capable of exhibiting a prolongedintegrity of the particles. Possibly, mucoadhesive properties areinferred to the particles, depending on the nature of the polymericcomponent. Possibly, these effects alone or in combination alsocontribute to, or are related to, the prolonged gastric residence timeof the particles, the increased bioavailability of the lipid(s) and theinduction of satiety caused by the particles' administration.

It has further surprisingly been found by the inventors that particlescontaining the water-swellable or water-soluble polymeric componentembedded in, or coated with, a lipid component comprising suchlow-melting fatty acid compound(s) is capable of forming a viscousemulsion in the gastrointestinal tract. Possibly, this effect alsocontributes, or is related to, the prolonged gastric residence time ofthe particles and the induction of satiety caused by theiradministration.

Optionally, the first lipid component may comprise one or more furtherconstituents which may have entirely different melting ranges. Forexample, a mixture of oleic acid, which has a melting range of 13° C. to14° C., and a hard fat (i.e. a mixture of triglycerides) having amelting range of 42° C. to 45° C. may be used as the first lipidcomponent. As an alternative to the hard fat, myristic acid (mp 54° C.to 55° C.) or lauric acid (mp 43° C. to 44° C.) may be used in suchmixture. It may also be advantageous to combine a fatty acid with thesalt of a fatty acid at a selected ratio such as to adjust the meltingrange to a desired optimum.

In one of the preferred embodiments, the fatty acid compound in thefirst lipid component, either per se in vitro or in the hydrated statein vivo, has a melting range of above 37° C. As used herein, the meltingrange is understood as being above 37° C. if the lower limit of therange is above 37° C. In other words, a compound having a melting rangeof 40° C. to 44° C. is an example of a material with a melting range ofabove 37° C. according to the invention. Moreover, the specified meltingrange is also met if the lipid component is capable of hydration,wherein the melting range in the hydrated state is still above 37° C. Aparticularly preferred first lipid component having a melting range ofabove 37° C. is fractionated but non-hydrogenated palm stearin or palmkernel stearin. Palm stearin is the solid fraction of palm oil that isproduced by partial crystallization at controlled temperature. Anexample of a preferred commercial quality is Prifex® 300 from Sime DarbyUnimills.

According to the invention, the water-swellable or water-solublepolymeric component is embedded within, and/or coated with, the lipidcomponent. As used herein, the term ‘embedded’ means that thewater-swellable or water-soluble polymeric component is largelydispersed within the lipid component, whether molecularly, colloidallyor in the form of a solid suspension. The lipid component forms acontinuous phase in which the water-swellable or water-soluble polymericcomponent is discontinuous and in dispersed form. For the avoidance ofdoubt, this does not exclude that some of the material representing thewater-swellable or water-soluble polymeric component—typically a smallfraction—is not fully embedded, but positioned at the outer surface ofthe lipid component.

Typically, ‘embedded’ also means in the context of the invention thatthe lipid component and the water-swellable or water-soluble polymericcomponent are mixed so intimately that the porosity of the resultinglipid-polymer composition is greatly reduced as compared to theparticles formed from the water-swellable or water-soluble polymeritself, for instance as formed by roller compaction or agglomeration.Particle porosity may be determined by porosimetry, an analyticaltechnique used to determine various quantifiable aspects of a material'sporous nature, such as pore diameter, total pore volume, and surfacearea. The technique involves the intrusion of a non-wetting liquid athigh pressure into a material through the use of a porosimeter.

The term ‘coated’ means that a particle comprising the water-swellableor water-soluble polymeric component is substantially surrounded with alayer of the lipid material representing the first lipid component. Inpractice, both forms (‘embedded in’ or ‘coated with’) may co-exist tosome degree, depending on the method of preparation.

In one of the preferred embodiments, the particle of the invention maybe designed to exhibit an active core and a coating covering the core,wherein the active core comprises the first lipid component with theembedded or coated water-swellable or water-soluble polymeric componentwhereas the coating comprises a second lipid component and/or ahydrophilic component. The coating may be substantially free of thewater-swellable or water-soluble polymeric component.

This embodiment is particularly useful in that the coating allows forconvenient oral administration without the water-swellable orwater-soluble polymeric component interacting with the mucosa of themouth or oesophagus during ingestion, as the coating acts as aprotective layer. The coating also provides protection againstagglomeration and sintering during manufacture, storage and shipping,and contributes to achieving an acceptable shelf life.

In other words, in this group of embodiments, the active core may becoated with a physiologically inactive coating, such as a polymeric filmcoating or a lipid coating. The polymeric film coating, which is basedon a hydrophilic component, may be free of lipid, or it may comprisesome relatively small amount of lipid e.g. as a plasticiser. The lipidcoating may be solely composed of the second lipid component, or it maycontain some amount of the hydrophilic component, e.g. as adisintegration enhancer.

The coating may be designed to be rapidly disintegrating so that theactive core of the particle is released rapidly after swallowing.Preferably, the second lipid component, i.e. that which is incorporatedin the coating of the particle, comprises one or more lipids having amelting point or melting range below about 37° C., as defined above,such as a melting range between about 25° C. and about 37° C. Thecomposition of the second lipid component may optionally be the same asthat of the first lipid component. Alternatively, it may be different.

As said, the coating of the particle according to this embodiment maycomprise a hydrophilic component. This hydrophilic material may beembedded or dispersed within the second lipid material and may act as adisintegration enhancer for the coating layer. Disintegrationenhancement may be achieved by various mechanisms, depending on thechoice of the hydrophilic component. For example, a disintegrant such ase.g. crospovidone, croscarmellose, low-substituted hypromellose or evenion-exchange resins may rapidly take up water, expand in volume andthereby cause the disruption of the coating. Non-swelling, highlywater-soluble excipients such as sugars or sugar alcohols, on the otherhand, may predominantly act as pore formers by which water channels arerapidly created by which disintegration is also enhanced. Optionally,the hydrophilic component comprises a mixture of hydrophilic compounds.Preferably, the hydrophilic component is different from thewater-swellable or water-soluble polymeric component and has no or onlya low degree of mucoadhesiveness.

If the coating only contains the hydrophilic component but no lipidcomponent, the hydrophilic component preferably represents afilm-forming agent such as a water-soluble polymer. Examples ofpotentially suitable film-forming polymers include methylcellulose,hyprolose, hypromellose, polyvinyl alcohol, povidone, polyvinyl acetate,(meth)acrylate copolymer, and the like. Optionally, the composition maycomprise further ingredients such as one or more plasticisers,pH-modifying agents, pore formers, colouring agents, sweetening agents,flavours, anti-tack agents, or dispersion aids.

In this group of embodiments, where the particle of the inventionexhibits an active core comprising the first lipid component with theembedded or coated water-swellable or water-soluble polymeric componentand surrounded by a coating, it is furthermore preferred that the activecore contributes at least about 50% to the weight of the total particle.Optionally, the weight of the active core is at least about 60%, or evenat least about 70% of the total particle's weight.

In a related embodiment, the particle according to the inventioncomprises an inert core, a first coating covering the inert core, and asecond coating covering the first coating. In this case, the firstcoating comprises the water-swellable or water-soluble polymericcomponent and the first lipid component, the second coating comprises asecond lipid component and optionally a hydrophilic component, and thesecond coating is also substantially free of the water-swellable orwater-soluble polymeric component. The hydrophilic component may beselected as described above. As in the previously discussed embodiment,the first lipid component with the embedded or coated water-swellable orwater-soluble polymeric component is surrounded with a coating layercomprising the second lipid component. The difference is that the firstlipid component and the water-swellable or water-soluble polymericcomponent do not form the core of the particle, but a layer on an inertcore having a different composition.

The inert core may be composed of a pharmacologically inert materialsuch as sucrose, starch or microcrystalline cellulose. Specific examplesof suitable inert cores include spheroids with average diameters in therange of about 100 or 200 μm based on microcrystalline cellulose whichare e.g. commercially available as Cellets® 100 or Cellets® 200;nonpareils of starch and sugar of similar diameter; or sugar crystals ofsimilar diameter, e.g. as obtainable by sieving.

With respect to the composition and further optional features of thelipid components, the water-swellable or water-soluble polymericcomponent and the hydrophilic component, reference is made to thediscussion above.

In the context of this embodiment, the inert core should preferably notcontribute more than about 70% to the weight of the total particle. Morepreferably, the weight of the core is not higher than about 60%, or nothigher than about 50% of the total particle weight. In otherembodiments, the weight of the core is from about 10% to about 50%, orfrom about 10% to about 40%, or from about 15% to about 35% of the totalparticle weight.

As already discussed, it is a key feature of the invention that thewater-swellable or water-soluble polymeric component is embedded within,or coated by, the first lipid component, which appears to effect animproved and/or prolonged interaction of the fatty acid with its targetat the gastrointestinal mucosa. A target structure may, for example, berepresented by G-protein coupled receptors (GPCRs) involved in thesensing of intestinal lipids such as GPR120.

In some embodiments, this may also result in an increasedbioavailability of the first lipid component. It may also result in anincreased bioavailability of the amino acid, the vitamin and/or themicro-nutrient if present. In this context, bioavailability should bebroadly understood such as to include the availability of e.g. the firstlipid component, or the biologically active constituents thereof, at abiological target site, such as the gastric or intestinal mucosa, interms of the extent and/or duration of availability.

Optionally, the particle may further contain an amino acid, a vitamin, amicro-nutrient, or any combinations of these.

As used herein, an amino acid is an organic compound having an aminogroup and a carboxyl group, mostly in the generic structure ofNH₂—CHR—COOH wherein R represents the side chain which is specific toeach amino acid. Optionally, the carboxylic group is partially or fullyneutralised. The amino acid may be provided in its L-form, its D-form orin its racemic form. In a preferred embodiment, the amino acid is aproteogenic amino acid, i.e. an amino acid which is a potentialprecursor of a protein in that it may be incorporated into a proteinduring its translation, or biosynthesis. Proteogenic L-amino acids ascurrently identified are L-alanine, L-arginine, L-asparagine, L-asparticacid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine,L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine,L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine,L-selenocysteine, L-pyrrolysine, and N-formyl-L-methionine. In anotherembodiment, the amino acid is selected from the 20 amino acids whichform the genetic code, which group consists of L-alanine, L-arginine,L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine,glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine,L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan,L-tyrosine, and L-valine.

In another preferred embodiment, the amino acid is selected from thegroup of the so-called essential amino acids which consists of thoseamino acids which the human organism cannot synthesise, i.e.L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine,L-phenylalanine, L-threonine, L-tryptophan, and L-valine.

In a further preferred embodiment, the amino acid is selected from thegroup consisting of L-isoleucine, L-valine, L-tyrosine, L-methionine,L-lysine, L-arginine, L-cysteine, L-phenylalanine, L-glutamate,L-glutamine, L-leucine, and L-tryptophan. From these, the groupconsisting of L-phenylalanine, L-leucine, L-glutamine, L-glutamate, andL-tryptophan is particularly preferred. In another preferred embodiment,the amino acid is L-tryptophan.

Optionally, the particle comprises two or more amino acids. Such mixtureor combination of amino acids should preferably comprise at least oneamino acid as described above, i.e. a proteogenic amino acid, or anamino acid from the group of amino acids forming the genetic code, orfrom the essential amino acids, or the group of amino acids consistingof L-isoleucine, L-valine, L-tyrosine, L-methionine, L-lysine,L-arginine, L-cysteine, L-phenylalanine, L-glutamate, L-glutamine,L-leucine, and L-tryptophan. Particularly preferred particles withmixtures or combinations of amino acids comprise at least one amino acidfrom the group consisting of L-phenylalanine, L-leucine, L-glutamine,L-glutamate, and L-tryptophan. In particular, L-tryptophan is apreferred constituent of a combination of two or more amino acids.

Also preferred are mixtures or combinations of amino acids in which atleast two amino acids are members of one of the preferred groups aspreviously defined. Moreover, mixtures or combinations of amino acidsmay be used in the particles of the invention in which essentially allincorporated amino acids are members of one of the preferred groups aspreviously defined.

As used herein, vitamins are vital nutrients required in small amounts,which e.g. humans (or other organisms) typically cannot synthesise insufficient quantities and which therefore must be taken up with thediet. The term ‘vitamin’ is conditional in that it depends on theparticular organism; for instance ascorbic acid is a vitamin for humans,while many other animals can synthesise it. Vitamins are organiccompounds classified by their biological and chemical activity, not bytheir structure. Each vitamin refers to a number of vitamers, all havingthe biological activity of the particular vitamin, convertible to theactive form of the vitamin in the body, and grouped together underalphabetised generic descriptors, such as ‘vitamin A’. Universallyrecognised vitamins are preferred for the present invention (relatedvitamers(s) in brackets): vitamin A (retinol, retinal, and thecarotenoids, including beta carotene, cryptoxanthin, lutein, lycopene,zeaxanthin), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3(niacin, niacinamide), vitamin B5 (pantothenic acid), vitamin B6(pyridoxine, pyridoxamine, pyridoxal), vitamin B7 (biotin), vitamin B8(ergadenylic acid), vitamin B9 (folic acid, folinic acid), vitamin B12(cyanocobalamin, hydroxycobalamin, methylcobalamin), vitamin C (ascorbicacid), vitamin D (cholecalciferol (D3), ergocalciferol (D2)), vitamin E(tocopherols, tocotrienols), vitamin K (phylloquinone, menaquinones).The vitamins according to the invention may be provided as semisyntheticand synthetic-source supplements and/or as supplements of naturalorigin; such as in the form of plant extracts.

As used herein, the term ‘micro-nutrients’ refers to nutrients requiredby humans and/or other organisms in small quantities for a variety oftheir physiological functions, their proper growth and development;including, for instance, dietary micro-minerals or trace elements inamounts generally less than 100 mg/day (as opposed to macro-minerals).The micro-minerals or trace elements include at least boron, cobalt,chromium, calcium, copper, fluoride, iodine, iron, magnesium, manganese,molybdenum, selenium, zinc. Micronutrients also include phytochemicals,such as terpenoids or polyphenolic compounds, as well as vitamins (i.e.some compounds may qualify for both categories, vitamins andmicro-nutrients).

Preferred micro-nutrients according to the invention may be selectedfrom organic acids, such as acetic acid, citric acid, lactic acid, malicacid, choline and taurine; and trace minerals such as salts of boron,cobalt, chromium, calcium, copper, fluoride, iodine, iron, magnesium,manganese, molybdenum, selenium, zinc, sodium, potassium, phosphorus, orchloride; and cholesterol.

The optional components, i.e. the amino acid, the vitamin and/or themicro-nutrient may be incorporated within the particles of the inventionin different ways. For example, hydrophilic compounds such as aminoacids, water-soluble vitamins and water-soluble micro-nutrients may beincorporated in admixture with the water-soluble or water-swellablepolymer, whereas lipophilic compounds may be incorporated in admixturewith the first and/or second lipid component.

To further enhance the beneficial effects of the particle, it ispreferred that the weight ratio of the first lipid component to thewater-swellable or water-soluble polymeric component is in the rangefrom about 0.1 to about 10. In some embodiments, the weight ratio isfrom about 0.1 to about 5, from about 0.1 to about 3, from about 0.1 toabout 2, or from about 0.1 to about 1. In further embodiments, thisweight ratio is from about 0.2 to about 1.5, from about 0.25 to about1.2, from about 0.25 to about 1.0, such as about 0.3, about 0.5, about0.75, or about 1, respectively. Particularly preferred is a weight ratiofrom about 0.5 to about 5, or from about 0.75 to about 4, or from about1 to about 3, respectively.

The inventors have found that the satiety-inducing effect of a free oresterified fatty acid is enhanced if delivered in the form of theparticle of the invention, which allows appetite suppression and theprevention and/or treatment of obesity even without pharmacologicalintervention using a synthetic drug. It is therefore a preferredembodiment that the particle is also free of a synthetic drug substance.In other words, the particle may substantially consist of thewater-swellable or water-soluble polymeric component and the first lipidcomponent, and optionally the second lipid component, the amino acid,the vitamin and/or the micro-nutrient and optionally one or morepharmacologically inert excipients such as the hydrophilic component oran inert core material.

The particle according to the invention may be in the form of a granule,a pellet, or a minitablet. More preferably, the particle is a granuleand/or a pellet.

As used herein, a granule refers to an agglomerated particle which hasbeen prepared from a plurality of smaller, primary particles.Agglomeration, or granulation, for the purpose of preparing a granule,may involve the use of a dry, wet or melt granulation technique.

A pellet, as used herein, is understood as a particle with a relativelyspherical or spheroidal shape. If prepared by an agglomeration process,a pellet is a special type of granule. However, pellets (i.e. sphericalor spheroidal particles) may also be prepared by other processes thanagglomeration. For the avoidance of doubt, the degree of sphericity of apellet may differ in various technical fields. In the context of theinvention, the sphericity of a pellet is in the typical range of pelletsused in pharmaceutical formulations for oral use.

A minitablet, often also referred to as a microtablet, is a unit formedby the compression or compaction of a powder or of granules. Typically,the compression is done on tablet presses using punches.

Minitablets, tablets or capsules comprising the particles of theinvention are preferably formulated and processed in such a way thatthey rapidly disintegrate after oral administration. As used herein,disintegration is understood as a substantial physical change to theminitablet, tablet or capsule morphology, such as the rupture ordetachment of the tablet's coating, the dissolution of a capsule or thedisintegration of a tablet or minitablet to release particles or pelletsor granules of the invention. For the detection of such tablet,minitablet or capsule disintegration behaviour, a microscope may beused. With respect to the apparatus, the hydrodynamic conditions, andthe temperature, the method <701> of the United States Pharmacopeia 29(USP29) may be used, except that water may be used as test medium andthat the wire mesh may be adapted with respect to the mesh size oraperture to take the sieve diameter of the tablet, minitablet or capsuleinto account. When tested according to this method, the minitablets ortablets or capsules comprising particles according to the inventionpreferably disintegrate within not more than about 15 minutes. Morepreferably, they disintegrate within about 10 minutes or less. Accordingto another embodiment, they disintegrate within about 8 minutes or less,or within about 5 minutes or less, respectively.

Particles according to the invention may be prepared by a methodcomprising a step of processing a mixture comprising the first lipidcomponent, the water-swellable or water-soluble polymeric component andoptionally the amino acid, the vitamin and/or the micro-nutrient by (a)extruding the mixture using a screw extruder; (b) spray congealing themixture, optionally using a jet-break-up technique; (c) melt granulatingthe mixture; (d) compressing the mixture into minitablets; (e) meltinjection of the mixture into a liquid medium; or (f) spray coating ofthe mixture onto inert cores.

The preparation of the mixture comprising the first lipid component, thewater-swellable or water-soluble polymeric component and optionally theamino acid, the vitamin and/or the micro-nutrient may be accomplished byconventional means such as blending or high-shear mixing. Optionally,the mixture is prepared using the same equipment which is also utilisedfor the subsequent step in which the particles are formed. For example,for preparing a melt to be used for melt congealing, melt granulation ormelt injection, it may not be required to prepare a dry premix prior tomelting the constituents of the melt, but the mixing and melting can beperformed simultaneously in one step. Therefore, the mixture to beprocessed according to steps (a) to (f) above should be broadlyinterpreted to cover any form of combining the materials required forpreparing the particles.

In one embodiment, the mixture is extruded using a screw extruder.Optionally, a twin-screw extruder is used for carrying out the extrusionstep. The extruder should have a screen with an aperture that is usefulfor producing an extrudate with appropriate diameter, such as 0.5 mm or1.0 mm. The screw speed may be selected in consideration of thecapability of the extruder and on the processability of the mixture. Forexample, it may be useful to select a screw speed in the range fromabout 20 to about 100 rpm.

Preferably, the extrusion step is carried out without the use of asolvent and at a relatively low temperature, such as below about 35° C.,or below about 30° C., e.g. at room temperature. It is also preferredthat the extrusion step is carried out at a temperature which is lowerthan the lower limit of the melting range of the lowest-meltingconstituent of the mixture.

It is also preferred that the ingredients used for preparing theparticles by extrusion are mixed or blended before they are fed to theextruder.

As mentioned above, the ingredients may also be mixed using the sameequipment which is utilised for the extrusion step. Thus, it is alsopreferred that the ingredients used for preparing extruded particles areprovided to the extruder by co-feeding, using appropriate feedingequipment, and optionally recycled within the extruder (e.g. viainternal bypass-loops) until a uniform mixture is obtained which isready for subsequent extrusion.

Subsequent to the extrusion step, the extrudate may be spheronised inorder to obtain approximately spherical particles. For this purpose, anyconventional spheroniser may be used. The temperature of the spheroniserjacket should preferably be set to be lower than the lower limit of themelting range of the lowest-melting constituent of the mixture. Thespeed of the spheronisation plates may be set between about 200 andabout 2,000 rpm, such as about 500 to about 1,500 rpm. Subsequentsieving may be performed in order to select an optimal particle size ofthe product.

In a particular embodiment, the particles are prepared from the mixtureby spray congealing. This process may also be referred to as spraychilling or spray cooling. In this process, a liquid melt is atomisedinto a spray of fine droplets of approximately spherical shape inside aspray cooling chamber. Here, the droplets meet a stream of air or gaswhich is sufficiently cold to solidify the droplets. The air or gasstream may have a co-current, mix-current or counter-current directionof flow.

To improve the formation of droplets of appropriate size and shape, aheatable rotary spray nozzle or a fountain nozzle may be used. In thecontext of the invention, a high speed rotary nozzle is one of thepreferred nozzle types for preparing the particles.

Optionally, the uniformity of the atomised droplets may be furtherenhanced by using a jet break-up technique, such as electrostaticdroplet generation, jet-cutting, jet excitation or flow focusing. Ingeneral, jet break-up refers to the disintegration of a liquid/gas jetdue to forces acting on the jet.

In electrostatic droplet formation processes, a nozzle equipped with anelectrode is used which applies an electrical charge to the melt spray.In jet cutting, the spray is directed through a cutter similar to e.g. arotary disc with apertures of defined size. Jet excitation means theexcitation of the melt spray by ultrasonic waves, causing vibration andfacilitating the separation of droplets.

Flow focusing results from combining hydrodynamic forces with a specificgeometry, which may be achieved by using a pressure chamber pressurisedwith a continuous focusing fluid supply. Inside, a focused fluid isinjected through a capillary feed tube whose extremity opens up in frontof a small orifice linking the chamber with the exterior ambient. Thefocusing fluid stream moulds the fluid meniscus into a cusp giving riseto a microjet exiting the chamber through the orifice. Capillaryinstability breaks up the stationary jet into homogeneous droplets.

In another specific embodiment, the particles are prepared by injectingthe melted mixture into a liquid. The liquid may be cooled to atemperature below room temperature, or preferably to substantially belowthe lower limit of the melting range of the lowest-melting constituentof the lipid component. The liquid should be selected taking thecomposition of the mixture into consideration, but also with an eye onsafety and physiological tolerability. In many cases, ethanol is asuitable liquid.

In another embodiment, the particles may be formed by meltagglomeration, or melt granulation. In the context of the invention,agglomeration and granulation may be used interchangeably. For thispurpose, the constituents of the mixture are mixed or blended andagglomerated, or granulated, in a suitable type of equipment, such as aheatable granulator, a high-shear mixer/granulator or a fluid bedgranulator. Depending on the type of equipment, the granulation may becarried out by heating the mixture to a temperature at which at leastone of its constituents softens or melts, under continuous stirring ormixing. In a conventional granulator, this may lead to largeragglomerates which are then passed through a sieve to obtain the desiredparticle size. If fluid bed equipment is used, the complete mixture maybe fluidised and heated carefully up to the melting temperature of thelowest-melting constituent. Alternatively, the lowest-meltingconstituent may be melted and sprayed onto the fluidised powder mixturecomprising the remaining constituents.

Optionally, the melt granules may be further processed and compressedinto minitablets. For this purpose, it is preferred that the granulesare first blended with one or more tablet fillers/binders to enhance theplasticity of the mixture. Moreover, conventional excipients to improvethe flow of the granules and reduce their tackiness may also be addedbefore compression. Tableting may be carried out using any conventionalpharmaceutical tablet press, such as an eccentric press or a rotarypress. Optionally, the press may be equipped with multi-punch tooling sothat each compression yields a plurality of minitablets. Punches forvery small tablet diameters are preferred, such as between about 1 mmand about 3 mm, such as about 1.5 mm.

In a further embodiment, the particles are prepared by spray coating themixture comprising the first lipid component and the water-swellable orwater-soluble polymeric component onto inert cores. As used herein, aninert core is a particle from a physiologically acceptable materialwhich is suitable for being coated, and which itself does notsubstantially contribute to the physiological effect of the particles ofthe invention, i.e. the induction of satiety. Examples of suitable coresinclude crystals of appropriate size and shape, such as sugar (sucrose)crystals. In one of the preferred embodiments, spherical beads ornon-pareils made from sugar, starch, cellulose, in particularmicrocrystalline cellulose (e.g. Cellets®) are spray coated with themixture.

The spray coating of the inert cores may, for example, be performed in afluid bed apparatus. The mixture of the first lipid component and thewater-swellable or water-soluble polymeric component may be melted andsprayed onto the fluidised core particles. Optionally, the amino acid,the vitamin and/or the micro-nutrient if present may also be added tothis mixture. Alternatively, an aqueous or organic dispersion (orsuspension, which is understood as a sub-type of a dispersion) of themixture is sprayed onto the fluidised cores in such a way that the wateror solvent evaporates and the mixture of the first lipid component andthe water-swellable or water-soluble polymeric component—and optionallythe amino acid, the vitamin and/or the micro-nutrient if present—forms acoating on the inert core particles.

As in all other processes mentioned above, a subsequent step ofclassifying the resulting particles using a sieve in order to obtain amore uniform particle size distribution may be useful.

For the preparation of particles according to the invention whichfurther exhibit a coating (or second coating covering the first coating)comprising a second lipid component and/or a hydrophilic component butnot the water-swellable or water-soluble polymeric component, suchsecond coating may also be applied using conventional pharmaceuticalspray coating techniques. In one of the preferred embodiments, fluid bedcoating is used for this purpose, using particles according to theinvention prepared as described above as active cores which arefluidised, and onto which either a melt or a dispersion/suspension ofthe second lipid component, or a solution or dispersion/suspension ofthe hydrophilic component is sprayed. If both the second lipid componentand the hydrophilic component are present, they may be applied togetherin the form of a dispersion/suspension in water or solvent, or as a meltof the lipid in which the hydrophilic component is dispersed.

According to a further aspect of the invention, an ingestible particleis provided which is obtainable by the method as described above.

In a further aspect, the invention provides a solid composition for oraladministration comprising a plurality of the particles as describedabove, or which has been prepared from a plurality of the particles,such as by compressing the particles into tablets. If not compressedinto tablets, the particles may in principle be filled into capsules,sachets, stick packs, or containers (e.g. bottles of glass or othermaterials). In one of the preferred embodiments, the granules are filledinto sachets, stick packs, or containers in such a way that a singledose is accommodated in one primary package. Optionally, the compositionmay comprise the particles along with one or more further inactiveingredients.

If the particles are to be swallowed as such, it is also preferred thatthey have a mass median sieve diameter in the range from about 0.1 mm toabout 3 mm. Also preferred are mass median sieve diameters in the rangefrom about 0.5 mm to about 3 mm, or from about 0.75 mm to about 2.5 mm,or from about 1 mm to about 2 mm. In other preferred embodiments, themass median sieve diameter may be in the range from about 0.1 mm toabout 0.4 mm, from about 0.2 mm to about 0.5 mm, or from about 0.2 mm toabout 0.4 mm, respectively.

The presentation and oral administration in the form of particles insachets, stick packs or containers is also useful as it is preferredthat a relatively large amount of the composition is administered as asingle dose. In one of the preferred embodiments, a single dosecomprises at least about 2 g of the composition, and more preferably atleast about 3 g thereof. In another embodiment, a single dose comprisesfrom about 3 g to about 20 g of the composition. In further embodiments,the amount comprised in a single dose is from about 4 g to about 15 g ofthe composition, or from about 5 g to about 12 g, or from about 5 g toabout 10 g, respectively. It is also preferred that the compositionexhibits a high contents of the particles of the invention, such as atleast about 50%, or at least about 60%, or at least about 70%, or atleast about 80% by weight. Particularly preferred is a particle contentin the composition of at least about 90%, or at least about 95%, or atleast about 98%, such as about 100% by weight.

For the purpose of administration, the composition may be suspended in aliquid or semisolid vehicle. The liquid may simply be water or fruitjuice or a dairy beverage or any other, preferably non-carbonated,ingestible liquid. It may optionally be provided together with thecomposition within a kit. This has the advantage that the nature andamount of liquid are controlled and the administration is morereproducible. The ready-to-use drink suspension may have, for example, avolume in the range from about 30 mL to about 300 mL, or from about 50mL to about 200 mL.

In a preferred embodiment, the composition of the invention isadministered as suspension drink. It was found that the suspension drinkof the invention is useful for administering large amounts, such as 1 gor more, of the composition while exhibiting good drinkability and mouthfeel. Drinkability of such a suspension drink according to the inventionmay be assessed by methods used to determine the flowability of wetgranular materials. In particular, dynamic measurements of the angle ofrepose may be taken using a rotating drum apparatus where the whole drumor its bottom and top are transparent or semi-transparent. Suchapparatus are commercially available for instance from MercuryScientific, USA (Revolution Powder Analyzer) and APTIS, Belgium(GranuDruM powder rheometer). In a suitable experimental set up fordynamic measurements of angle of repose of wet granular materialcomprising aqueous liquid, the drum is preferably made of PTFE (Teflon®)or coated with PTFE or similar anti-adhesive material, and is filled tohalf of its volume with a suspension of powder or particles. Afterplacing the drum's top and bottom along a horizontal axis, and repeatedtapping for even distribution of the drum's contents, the suspensionforms a horizontal meniscus of an angle of zero. This may be visuallyobserved and measured by standard methods of angle measurements.Rotating the drum along this horizontal axis may displace the meniscusof the powder suspension to a certain angle before the meniscus of thesuspension repositions itself to an angle of almost zero. Thedisplacement of the meniscus from the horizontal may be repeated severaltimes, and a mean value of the dynamic angle of repose may becalculated.

Preferably the suspension drink comprises a plurality of the particlesof the invention and at least one aqueous liquid, and the sum of thevolume fractions of the particles and the at least one aqueous liquidmakes 100 vol-%. Accordingly, the present invention provides asuspension drink, comprising 50 to 75 vol-% of particles according tothe invention; and 25 to 50 vol-% of at least one aqueous liquid;wherein the volume fractions are based on the total volume of thesuspension drink. Preferably, the dynamic angle of repose of thesuspension drink is less than about 30°.

In a further preferred embodiment, the amounts of particles and liquidare selected such that a densely packed suspension drink is obtained bymatching the filling height of the particles settled in a suitably sizedcontainer with the filling height of the aqueous liquid in the samecontainer comprising the settled particles. In other words, the amountof the liquid is chosen in such manner that the meniscus of the liquidis roughly at the position of the upper limit of the settled particles.

The at least one aqueous liquid further may comprise alcohol, flavouringcompounds, colouring compounds, preservatives, viscosity enhancers,health ingredients or mixtures of two or more thereof. Suitableflavouring compounds are citric acid, malic acid, phosphoric acid,tartaric acid, natural and synthetic aroma, sweeteners, for examplemonosaccharides, disaccharides, polyhydric alcohols; including arabitol,erythritol, glycerol, isomalt, lactitol, maltitol, mannitol, sorbitol orxylitol; or sugar substitutes, including cyclamate, saccharine, stevia,sucralose and/or aspartame. Further suitable flavouring compounds arejuices of fruits and/or vegetables. Colouring compounds suitable for theaqueous liquid are for example Allura Red AC, Anthocyanine, azorubine,betanin, Brilliant Blue FCF, carotene, Quinoline Yellow WS, Ponceau 4R,Green S, Patent Blue V and tartrazine, either as such or in the form ofthe corresponding aluminium lakes. Suitable preservatives are vitaminsA, E or C, retinyl palmitate, cysteine, methionine, citric acid, sodiumcitrate, used in amounts of 0.001 to 0.1% by weight based on the liquid.

The amount of the first lipid component, which is a key ingredient ofthe composition, should preferably be at least about 1 g per single doseor per package. In another embodiment, a single dose comprises at leastabout 2 g of the first lipid component, such as about 3 g or about 4 g.In a further preferred embodiment, the content of the first lipidcomponent per single dose is at least about 5 g.

The amount of the amino acid (or of the total amino acids, if a mixtureor combination of amino acids is used) may be about 0.05 g or more persingle dose or per package. In another embodiment, a single dosecomprises at least about 0.1 g, or at least about 0.2 g, or at leastabout 0.5 g of amino acid(s), respectively. In further embodiments, thecontent of the amino acid(s) per single dose is from 0.5 g to about 5 g,or from 0.5 g to about 3 g.

In one of the embodiments, the components of the particles are selectedsuch that the dynamic angle of repose of a suspension prepared fromsuspending the composition in water at a weight ratio of 1 is less than30°.

As mentioned, the particles and the compositions of the invention may beused for the suppression of appetite, in particular in human subjects,and for the induction of satiety.

Without wishing to be bound by theory, it is currently believed by theinventors that the appetite suppressing effect is at least in part basedon the fatty acid compound comprised in the first lipid component, whichupon ingestions interacts with physiological targets located in themucosa of the gastrointestinal tract, such as in the stomach and/orduodenum, thereby activating one or more signalling cascades whicheventually produce a perception of satiety or a reduction of appetite orhunger. Possibly, one of the targets at which the fatty acid acts arethe ghrelin cells (or ghrelin receptors), large numbers of which arelocated in the stomach and the duodenum.

If present, the amino acid may further contribute to the appetitesuppressing effect, which may be due to a stimulation of chemosensors inthe proximal gastrointestinal tract by which in turn the CCK andglucagon secretion is triggered.

The water-swellable or water-soluble polymeric component was found bythe inventors to enhance the effect of the fatty acid which is possiblydue to the swelling and/or mucoadhesive properties effecting a prolongedattachment of the particles (or components thereof) to the gastric orduodenal mucosa, allowing for an increased interaction of the fatty acidwith the target structure. Of course, other properties of the particlesmay also effect or contribute to a prolonged gastric residence time,such as the selected particle size or the low density resulting from thehigh lipid content. In any case, the inventors found that the oraladministration of the particles to volunteers induced satiety with theconsequence that the subjects experienced suppressed appetite and showeda reduced food intake during the meal following the administration of acomposition comprising the particles as described herein. This effectwas consistent with animal data showing the composition leads to aweight loss, or weight reduction, of the test animals.

The particles and/or compositions of the invention may therefore be usedclinically, or as dietary supplements, for the prevention and/ortreatment of obesity and overweight, as well as the prevention and/ortreatment of diseases or conditions associated with obesity; e.g. byusing the ingestible particles as defined herein and/or compositionscomprising or prepared from a plurality of these particles for bodyweight reduction.

In other words, one aspect of the invention provides a method for theprevention and/or treatment of obesity and overweight, as well as theprevention and/or treatment of diseases or conditions associated withobesity, for appetite suppression, body weight reduction and/or for theinduction of satiety, said method comprising a step of orallyadministering the particles of the invention and/or compositionscomprising or prepared from a plurality of these particles. Optionallysaid method comprises the oral administration of the particles and/orcompositions at least once a day over a period of at least one week.

In yet other words, one aspect of the invention provides the use of theparticles of the invention and/or compositions comprising or preparedfrom a plurality of these particles in the manufacture of medicamentsfor the prevention and/or treatment of obesity and overweight, as wellas the prevention and/or treatment of diseases or conditions associatedwith obesity, for appetite suppression, body weight reduction and/or forthe induction of satiety. Optionally, this comprises the oraladministration of the particles and/or compositions at least once a dayover a period of at least one week.

As used herein, obesity is a medical condition in which excess body fathas accumulated to the extent that it may have an adverse effect onhealth. Overweight is understood as a borderline condition characterisedby a body mass index (BMI) between 25 and below 30. Starting from a BMIof 30, the condition is classified as obesity.

In one embodiment, the particles and/or compositions are administered tonormal weight or overweight subjects gaining weight over time orotherwise being at risk of developing obesity. In this case, thetherapeutical objective is to stop or limit the weight gain and preventthe development of obesity. Another purpose may be to reduce the riskthat the subject develops a disease or condition associated with orcaused by obesity.

In a further embodiment, the particles and/or compositions areadministered to obese patients in order to treat or reduce the severityof obesity. Again, the therapeutic use may also be directed to thereduction of the risk of developing a disease or condition associatedwith or caused by obesity.

A large number of diseases and conditions are nowadays considered to beassociated with or caused by obesity, even though the mechanism by whichthey are linked to obesity may not always be fully understood. Inparticular, these diseases and conditions include—withoutlimitation—diabetes mellitus type 2, arterial hypertension, metabolicsyndrome, insulin resistance, hypercholesterolaemia,hypertriglyceridaemia, osteoarthritis, obstructive sleep apnoea,ischaemic heart disease, myocardial infarction, congestive heartfailure, stroke, gout, and low back pain. The prevention and/orreduction of risk for developing any of these conditions is within thescope of the therapeutic use according to the invention.

Moreover, the therapeutic use preferably involves the at least oncedaily oral administration of the particles and/or compositions of theinvention over a period of at least one week. In this context, theexpression “therapeutic use” is understood to also cover the preventiveor prophylactic use. In a further preferred embodiment, the particlesand/or compositions are administered to a human subject over a period ofat least about 2 weeks, or at least about 4 weeks, or at least about 6weeks, or at least about 2 months, respectively. Also preferred is anadministration regimen providing for once or twice daily administration.

The time of administration should be selected to maximise thesatiety-inducing effect on the amount of food which is subsequentlytaken up by the subject that is treated. For example, it is useful toadminister a dose of the composition before a major meal, such as beforea lunchtime meal and/or before the evening dinner such as to reduce theamount of food eaten during either of these meals. With respect to theprecise timing, it is preferred that the dose is administered withinabout 5 to 120 minutes prior to the respective meal, in particular about10 to about 120 minutes prior to the meal, or about 15 to about 90minutes prior to the meal, such as about 30 or about 60 minutes prior tothe meal.

In one of the particularly preferred embodiments, a dose comprising atleast about 5 g of the first lipid component is administered to a humansubject at least once daily between about 15 and about 90 minutes priorto a meal over a period of at least 4 weeks for the prevention and/ortreatment of obesity or an associated disease.

It is further contemplated that the particles and/or compositions of theinvention are used in combination with the use of a device for thecollection, storage and/or display of information relating to asubject's adherence to the therapy and/or the effectiveness of thetherapy. As used herein, information relating to a subject's adherenceto the therapy may include, for example, information on whether a dosewas administered within a certain period of time (e.g. during a calendarday), or the time at which each dose was administered. The device ispreferably a programmed electronic device, such as a computer, inparticular a microcomputer, and most preferably a portable microcomputersuch as a mobile phone (“smartphone”), or a wearable device such as asmart watch, an electronic wristband, or the like. The information maybe received by the device automatically from a sensor, or it may beentered manually by a user, such as the subject or patient, thephysician, nurse, or by a caregiver, and stored for subsequent analysisor display. For example, the patient may periodically monitor his or heractual compliance or adherence to the therapy.

The device may be programmed to provide the user with a feedback signalor reminder in case of non-compliance or lack of adequate adherence tothe therapy. The feedback signal may be optical, haptic (e.g.vibration), or acoustic.

Information relating to the effectiveness of the therapy may include,for example, the weight of the subject, the degree of hunger orappetite, the number of meals and snacks, or the type or amount of foodeaten during any particular period of time (e.g. a calendar day), oreven physiological data such as the blood glucose concentration or bloodpressure. Depending on its type, the information relating to theeffectiveness of the therapy may be automatically received by the deviceor entered manually by the user. Information with respect to the feelingof satiety or hunger may be usefully entered by the user or patient in amanual mode, whereas physiological parameters such as blood glucose orblood pressure may be received from the respective measuring devicesused for their determination. In the latter case, the transfer of thedata encoding the information generated by the measuring device to thedevice for the storage and/or display of the information is preferablywireless.

In more detail, information collection may be user-initiated or thedevice may be programmed with an application (i.e. software) whichcreates an alert calling for the user to input her or his satiety-stateinformation. Preferably, information collection proceeds in regular timeintervals such as 15 or 30 min intervals. In one embodiment, informationcollection is performed throughout a period of 12, 16 or 18 hours perday. In another embodiment, information collection is performed inmultiple periods of for instance 1 to 3 hours over the day, for instancethree times for 3 hours each. Preferably such time periods cover mealtimes such as breakfast, lunch and dinner. Preferably, users—for a givenperiod of information collection—may not refer to previous satietyratings when providing the real-time information.

Information collection may proceed in the following fashion. After theuser has opened the software application, a satiety state screen isdisplayed on the colour touch screen using visual analogue scales forthe assessment of satiety. Such scales and scores have previously beendescribed in detail [Flint A, Raben A, Blundell J E, Astrup A.Reproducibility, power and validity of visual analogue scales inassessment of appetite sensations in single test meal studies. Int JObes Relat Metab Disord 2000; 24:38-48). In brief, the visual analoguescale (VAS) consists of a horizontal, unstructured, 10 cm line withwords anchored at each end, describing the extremes (‘not at all’ or‘extremely’) of the unipolar question, ‘How satiated are you right now?’To ensure reliable and valid results, participants rate their feeling ofsatiation as precisely as possible, and they cannot refer to theirprevious ratings when marking the VAS.

The satiety state screen may display a query 1 “how hungry do you feel?”combined with an unstructured sliding scale labelled “I am not hungry atall” on one end to “very hungry” on the other hand. The application willwait for the user to touch the sliding scale at one position. Upontouching the scale, a slider may appear, and the user may adjust itsposition. The application will determine the position of the sliderafter the user removed its touching finger from the slider symbol,retrieve the positional value and use it for further processing.

Further potentially useful embodiments are easily derivable on the basisof the guidance provided herein-above and the following examples.

Examples Example 1: Preparation of Particles by Spray Congealing

Particles with a water-swellable or water-soluble polymeric componentembedded within a lipid component may be prepared by spray congealing asfollows. 250 g of capric acid are melted. 100.0 g of carbomerhomopolymer type A NF and 50.0 g of sodium caprate are added to the meltand mixed such as to form a viscous suspension. Under continuousheating, the suspension is fed to the heated rotary nozzle of a spraycongealing tower. Cold air is continuously introduced into the tower toallow solidification of the resulting droplets. The solid particles arethen passed through appropriate sieves to allow removal of oversize andundersize particles, and to obtain particles according to the invention.Optionally, the product may be further processed, e.g. by coating theparticles.

Example 2: Preparation of Particles by Spray Congealing

Similarly, particles may be prepared from polycarbophil and a mixture offatty acids. For example, 240.0 g of lauric acid and 60.0 g of capricacid are melted, and 100.0 g of polycarbophil (USP) are incorporatedinto the melt such as to obtain a viscous lipid suspension. Undercontinuous heating, the suspension is fed to the heated rotary nozzle ofa spray congealing tower. Again, cold air is continuously introducedinto the tower to allow solidification of the resulting droplets.Subsequently, the solidified particles are passed through appropriatesieves to allow removal of oversize and undersize particles, and toobtain particles according to the invention.

Example 3: Preparation of Particles by Spray Congealing Using JetBreak-Up Techniques

As a variation of Example 1, a spray congealing tower may be used whichis equipped for a jet break-up spray process to generate monodisperseparticles of appropriate size, e.g. electrostatic droplet generation,jet-cutter technology, jet excitation, or flow focusing. 200.0 g of hardfat EP/NF (e.g. Suppocire® A) and 400.0 g of sodium myristate are mixedand melted. 100.0 g of carbomer homopolymer type B NF added to the meltand mixed such as to form a viscous suspension. Under continuousheating, the suspension is fed to a nozzle of a spray congealing towerwith jet excitation equipment. The vibration excitation is set toprovide particles in the range of 200 μm. Cold air is continuouslyintroduced into the tower to allow solidification of the resultingdroplets. The uniform, solidified particles are collected as finalproduct.

Example 4: Preparation of Particles by Melt Injection

150.0 g of a mixture of hard fat EP/NF and glyceryl monooleate (type 40)EP/NF (e.g. Ovucire® WL 2944) and 200.0 g of sodium laurate are mixedand melted. 90.0 g of carbomer interpolymer type A NF added to the meltand mixed such as to form a viscous suspension. Under continuousheating, the suspension is fed to the needle of an elementarymicrofluidics device, through which droplets are formed and injectedinto cooled absolute ethanol to provide particles in the 250 μm range.The solidified particles are collected and thoroughly dried to result inthe final product.

Example 5: Preparation of Particles by Solvent-Free Cold Extrusion

An intimate mixture of 250.0 g of hardened palm oil, 50.0 g of sodiumoleate and 110.0 g of carbomer 941 NF is prepared using a V-blender. Theblend is fed by a gravimetric powder feeder type KT20 (K-Tron) to thepowder inlet opening of a Leistritz NANO 16® twin screw extruder andextruded in the first segments at a temperature range between 25° C. and30° C. The final segment is cooled to 20° C. Short rods of approx.0.8-1.5 mm length are obtained by this process. The rods aresubsequently spheronised in a Caleva® MBS 120 equipment, with waterjacket temperature set to 30-35° C., until the final product is obtainedin the form of essentially spherical particles.

Example 6: Coating of Sugar Crystals by Melt Granulation

A premix of 200.0 g of myristic acid, 75.0 g of sodium oleate, 100.0 gof carbomer 941 NF and 250.0 g of sucrose crystals (mean particle size200-250 μm) is prepared. The premix is introduced into a planetary mixerequipped with a heatable jacket. Under continuous operation of themixer, the temperature is slowly raised until the lipid phase isthoroughly molten. Again under continuous operation of the mixer, thetemperature is cooled to room temperature. The resulting solidified massis passed through a sieve to break or remove oversized particles, givingthe final product.

Example 7: Coating of Non-Pareil Seeds by Organic Lipid Solution

A premix of 200.0 g of myristic acid, 75.0 g of sodium oleate, and 100.0g of carbomer 941 NF is prepared and dispersed in absolute ethanol.275.0 g of sugar spheres EP/NF (non-pareils) are introduced into anexplosion-proof fluid bed equipment with Wurster column and pre-heatedto 50-55° C. Subsequently, the dispersion is slowly sprayed onpre-heated sugar spheres, allowing for evaporation of the ethanol, andtaking into account the critical explosion limit of air-ethanolmixtures. At the end, the coated sugar spheres are cooled to roomtemperature and flushed with cold air until the limit of residualsolvents is within acceptable limits, to provide the final product.

Example 8: Coating of Non-Pareil Seeds by Aqueous Suspension

A premix of 300.0 g of myristic acid and 100.0 g of carbomer 941 NF isprepared and dispersed in demineralised water (q.s.). In analogy to theprevious example, 275.0 g of sugar spheres EP/NF (non-pareils) areintroduced into a fluid bed equipment with Wurster column and pre-heatedto approx. 50-55° C. Subsequently, the suspension is slowly sprayed onthe pre-heated sugar spheres to allow the water to evaporate. At theend, the coated sugar spheres are cooled to room temperature and flushedwith cold air until the limit of residual water is within acceptablelimits, to provide the final product.

Example 9: Compression of Minitablets from Melt Granulate

Particles according to the invention may also be prepared in the form ofminitablets, preferably with a small diameter, such as 1.5 mm. Forexample, 300.0 g of lauric acid, 50.0 g of sodium laurate, 100.0 g ofmicrocrystalline cellulose (e.g. Avicel® PH101), and 100.0 g of carbomer941 NF are mixed to obtain a premix which is then introduced into ajacketed, heated planetary mixer, and agglomerated to result in agranular material. The melt granulate is then sieved through anappropriate sieve equipped with knives to result in a fine, granularmaterial. This granular material is subsequently blended with 75.0 g ofmicrocrystalline cellulose (e.g. Avicel® PH101). The resulting blend iscompressed on a multi-punch eccentric tablet press into biconvex tabletswith a diameter of 1.5 mm and thickness of approx. 2 mm, to provide thefinal product. In this example, the microcrystalline cellulose may alsobe replaced by lactose (e.g. lactose monohydrate NF) or calcium hydrogenphosphate dihydrate (Ph.Eur.).

Example 10: Coating of Active Cores with a Film Coating Based onHypromellose

Active cores prepared according to Examples 1 to 9 may be coated asfollows. An aqueous polymer solution (A) is prepared by dissolving 5.0 gof hypromellose type 2910 (e.g. Pharmacoat® 603) in 90.0 mL ofdemineralised water. Separately, a pigment dispersion (B) is prepared bydispersing 2.0 g of titanium dioxide (e.g. Titanium Dioxide “Anatas”)and 1.0 g of a pigment in 15.0 mL of demineralised water, followed byhomogenisation using a high-shear homogeniser. Subsequently, a coatingdispersion (C) is prepared by mixing the polymer solution (A) and thepigment dispersion (B) under continuous stirring.

In the next step, 1,000 g of the active cores prepared according to anyone of Examples 1 to 9 are fluidised in a fluidised bed granulationapparatus equipped with a Wurster column at a temperature of 25-30° C.100 mL of the coating dispersion (C) are slowly sprayed on the activecores, keeping the bed temperature at 25-30° C. by adjusting inlet airtemperature and spray rate. The coated active cores are fully dried atthe same temperature within the fluidised bed, and thereafter cooled toroom temperature within the fluidised bed.

In result, coated particles will be obtained whose coating rapidlydisintegrates after oral ingestion.

It is noted that the polymer solution (A) may also be prepared bydissolving 5.0 g of hypromellose type 2910 (e.g. Pharmacoat® 603) in amixture of 45.0 mL of ethanol and 55.0 mL of demineralised water. Thisvariation would lead to a more rapid evaporation of the solvent duringthe spray coating process.

Alternatively, a coating dispersion may also be prepared by furtherincorporating a plasticiser, a surfactant, and a small amount ofethylcellulose. In this case, a polymer solution (A) may be prepared bydissolving 5.0 g of hypromellose type 2910 (e.g. Pharmacoat® 603) and0.5 g of triacetin (glycerol triacetate) in 50.0 mL of demineralisedwater. In addition, 0.25 g of sodium lauryl sulphate are dissolved in2.5 mL of demineralised water to form a surfactant solution (A′). Apigment dispersion (B) is prepared by dispersing and homogenising 2.5 gof talc, 3.0 g of titanium dioxide and 0.2 g of colorant pigment in 20.0mL of demineralised water. Subsequently, the coating dispersion (C) isprepared by mixing the polymer solution (A), the surfactant solution(A′), the pigment dispersion (B), and 5.0 g of an ethylcellulosedispersion (corresponding to 1.5 g dry matter). The coating procedureitself is conducted as described above.

Example 11: Preparation of a Composition Comprising Coated Particles

A composition comprising the particles of the invention which may easilybe filled into stick packs or sachets may be obtained from gently mixing1,005 g of the coated active cores prepared according to Example 10 with0.5 g of hydrophobic colloidal silica (NF) (e.g. AEROSIL® R 972) in arotating drum. Instead of hydrophobic colloidal silica, a standard gradeof colloidal silicon dioxide (e.g. AEROSIL® 200) may also be used at thesame amount. In this composition, the silica acts as anti-tacking agent.

Example 12: Coating of Active Cores with a Mixture of a Lipid Componentand a Hydrophilic Component

A coating dispersion is prepared by dissolving 5.0 g of hypromellosetype 2910 (e.g. Pharmacoat® 603) and dispersing 2.0 g of lauroylpolyoxyl-32 glycerides NF (e.g. Gelucire® 44/14) in a mixture of 45.0 mLof ethanol and 55 mL of demineralised water. Subsequently, 105 mL of thedispersion is coated on 1,000 g of the active cores prepared accordingto any one of Examples 1 to 9, using the same equipment and procedure asin Example 10. Coated particles according to the invention are providedwhich exhibit rapid disintegration of the coating after oraladministration.

As alternatives to the lauroyl polyoxyl-32 glycerides NF, similaramounts of stearoyl polyoxyl-32 glycerides NF (e.g. Gelucire® 50/13) orcaprylocaproyl polyoxyl-8 glycerides NF (e.g. Labrasol®) may be used.

Example 13: Coating of Active Cores with a Film Coating Based onPovidone

A coating solution may be prepared by dissolving 5.0 g of povidone K30and 1.0 g of polyethylene glycol 4000 (alternatively polyethylene glycol1000) in a mixture of 60 mL of ethanol and 40 mL of demineralised water.100.0 mL of the solution are then sprayed onto 1,000 g of the activecores prepared according to any one of Examples 1 to 9, using the sameequipment and procedure as in Example 10. The procedure leads toparticles whose coating rapidly releases the active core after oraladministration.

Example 14: Coating of Active Cores with a Film Coating Based on EthylCellulose

A coating solution may be prepared by dissolving 4.0 g of ethylcelluloseNF (e.g. ETHOCEL® 10 FP) and 1.0 g of polyethylene glycol 4000 in amixture of 25 mL of acetone, 35 mL of ethanol and 40 mL of demineralisedwater. 100.0 mL of the solution are then sprayed onto 1,000 g of theactive cores prepared according to any one of Examples 1 to 9, using thesame equipment and procedure as in Example 10, and taking into accountthe critical explosion limit of air-acetone-ethanol mixtures. Theprocedure leads to particles whose coating rapidly releases the activecore after oral administration.

Example 15: Coating of Active Cores with a Coating Based onPhospholipids

In this Example, the coating comprises a lipid component in combinationwith a hydrophilic component. A coating suspension is prepared bydispersing 10.0 g of partially hydrogenated soybean lecithin (e.g.Lipoid S75-35 or Lipoid S-PC-35) in demineralised water (q.s.), usinghigh shear homogenisation, followed by the addition of a small amount(q.s.) of an immediate release coating system (e.g. Opadry®) containinga water-soluble coating polymer, a plasticiser and pigment. 100.0 mL ofthe dispersion are then sprayed onto 1,000 g of the active coresprepared according to any one of Examples 1 to 9, using the sameequipment and procedure as in Example 10. The procedure leads toparticles whose coating rapidly releases the active core after oraladministration.

To obtain coated particles with reduced stickiness, a portion of thepartially hydrogenated soybean lecithin may be replaced by a fullyhydrogenated lecithin (e.g. Lipoid S75-3), or 2.0 g of the fullyhydrogenated lecithin may be incorporated in addition to the 10.0 g ofpartially hydrogenated soybean lecithin.

Example 16: Coating of Active Cores with a Mixture of Lecithin andMaltodextrin

10.0 g of a powder mixture of lecithin and maltodextrin (e.g. Soluthin®)is dispersed in 95 mL of demineralised water at room temperature. 1,000g of the cores prepared according to any one of Examples 1 to 9 arefluidised bed apparatus at a temperature of 20 to 30° C. Subsequently,100.0 mL of the dispersion are slowly sprayed on the active cores by thetop spraying procedure, keeping the bed temperature at 20-30° C. byadjusting inlet air temperature and spray rate. The coated cores arefully dried at the same temperature within the fluidised bed, andthereafter cooled to room temperature within the fluidised bed. Again,coated particles are obtained which release their active core rapidlyafter oral administration.

Example 17: Coating of Active Cores with a Sucrose Ester

A clear solution is prepared by dissolving 15.0 g of sucrose laurateL-1695 in 90.0 mL of demineralised water at room temperature. 1,000 g ofthe active cores prepared according to any one of Examples 1 to 9 arefluidised and coated in a similar manner as described in Example 16 toobtain coated particles with similar properties with respect to theirrelease behaviour.

As an alternative to sucrose laurate L-1695, sucrose laurate L-1570 maybe used, optionally in the form of sucrose laurate LWA-1570, aready-to-use solution of 40% L-1570 in 4% ethanol and 56% water. Forexample, 30.0 g of sucrose laurate LWA-1570 may be diluted with 110.0 mLof demineralised water and 20 mL of ethanol. 150 mL of this coatingsolution may be used to coat 1,000 g of the cores.

Example 18: Coating of Active Cores with Ethylene Glycol/Vinyl AlcoholGraft Copolymer

Coated particles according to the invention may also be prepared byusing ethylene glycol/vinyl alcohol graft copolymer as an immediaterelease coating agent. For instance, a polymer solution may be preparedfrom 24.0 g of Kollicoat® which are dispersed 96 mL of demineralisedwater and dissolved under stirring. Separately, a pigment suspension isprepared by dispersing 4.5 g of talc, 1.5 g of iron oxide red, and 3.9 gof titanium dioxide in 11.0 mL of demineralised water, followed byhomogenisation with a high shear homogeniser. The coating dispersion isthen obtained by mixing 100.0 mL of the polymer solution with 20.0 g ofthe pigment suspension. 1,000 g of the active cores prepared accordingto any one of Examples 1 to 9 are fluidised and coated in a similarmanner as described in Example 16 to obtain coated particles withsimilar properties with respect to their release behaviour. During thewhole coating process, the coating suspension is continuously stirred toavoid sedimentation.

Example 19: Preparation of Particles by Cryomilling

300 g hard fat (adeps solidus from Caelo, Germany) were brought to amelt at 50° C. 200 g Carbopol® 971G (Lubrizol) were incorporated intothe lipid by means of a spatula. The viscous mass was filled into aplastic bag and cooled to −18° C. in a freezer. The frozen material wascrushed with a hammer and shredded to a powder in a kitchen blender(Bosch ProfiMIXX, Germany). After drying under vacuum at 25° C. toremove residual condensed water, the obtained particles were classifiedthrough a set of wire mesh sieves (VWR International, Germany) toprovide a classified powder having a size of below 0.5 mm.

Example 20: Preparation of Particles by Cryomilling

500 g hard fat (Witepsol® W35 from NRC, Germany) were brought to a meltat 50° C. 250 g Carbopol® 971G (Lubrizol) were incorporated into thelipid by means of a spatula. The viscous mass was filled into a plasticbag and cooled to −18° C. in a freezer. The frozen material was crushedwith a hammer and shredded to a powder using an ultra-centrifugal mill(ZM 200, Retsch, Germany). For milling, the material was precooled usingdry ice, and a rotation speed of 18000/min was applied for two minutes.The material was quantitatively converted to particles with a diameter(D90) of 0.2 mm. Prior to classifying the particles, they were driedunder vacuum at 25° C. to remove residual condensed water, where thiswas considered expedient.

Example 21: Preparation of Particles by Fluid-Bed Granulation

400 g of the classified powder from Example 19 were loaded into a fluidbed device (Ventilus V-2.5/1 from Innojet, Germany) equipped with a IPC3product reservoir. The powder was fluidised at 32° C. using an air flowof 50 m³/h. The material was granulated for 30 min and classifiedthrough a set of wire mesh sieves to obtain 240 g of particles of a sizebetween 0.5 and 1.0 mm, and 64 g of particles of a size above 1.0 mm.

Example 22: Animal Studies A. General Procedures

Animals (rats) were kept in cages on standard animal bedding (twoanimals per cage or individual housing) and were provided with adlibitum access to food and water. Animal food was provided as pellets ina pellet rack or as a cream or as granulate powder in a containerattached to the inside of the cage.

Body weight was recorded at beginning and end of experiments. Foodconsumption was documented daily except for weekends. Experiments wereperformed according to German laws of animal protection.

Rodent chow was purchased from Ssniff® Spezialdiäten GmbH, Germany andpoly(acrylic acid) (PAA, Carbopol® 971 P NF) was obtained from theLubrizol Corporation, USA. Cocoa butter chips (Caelo 633B) were fromCaesar & Lorentz, Germany. Hard fat (Witepsol®) was from NRC, Germany.All percentages provided are w/w-percentages, unless specificallymentioned otherwise.

B. Standard Pellet Chow with 5% Fat—Reference for Normal Food Uptake andWeight Gain

Twelve male wistar rats having a mean body weight of 319±7 g were fed anexperimental diet provided as pellets for seven days. The mixture wascomposed of standard chow diet (Ssniff® EF R/M Control, 5%) having a fatcontent of 5% in the final mixture.

Water was added to the standard chow to produce a paste which wasextruded and cut into pellets (1 cm×3 cm) by means of a food processor(Kitchen Aid Classic, USA). Pellets were dried at 25° C. over night.

At the end of the experiment, food intake, energy intake and body weightchange were calculated (±SD). Animals gained 5.0±1.9% body weight, meandaily food intake was 24.3±2.7 g, representing a mean metabolisableenergy intake of 374±40.8 kJ per animal per day.

C. Pellet Chow/Cocoa Butter Composition with 11.6% Fat—Reference forCalorie-Adjusted Food Uptake

Six male wistar rats having a mean body weight of 324±6 g were fed anexperimental diet provided as pellets for six days.

The mixture was composed of standard chow diet (Ssniff® EF R/M Control,5%) and cocoa butter (7.5% relative to the standard chow weight),resulting in approx. 11.6% fat in total (including cocoa butter) andapprox. 7.0% cocoa butter relative to the final mixture. Cocoa butterwas melted and blended with standard chow. Water was added to produce apaste which was extruded and cut into pellets (1 cm×3 cm) by means of afood processor (Kitchen Aid, USA). Pellets were dried at 25° C. overnight.

At the end of the experiment, food intake, energy intake and body weightchange were calculated (±SD). Animals gained 3.8±1.3% body weight, meandaily food intake was 22.5±2.0 g, representing a mean metabolisableenergy intake of 382.2±33.7 kJ per animal per day.

D. Cream-or Paste Chow Composition with 50% Fat Limited to 10 g/Day PerAnimal—Reference for Weight Loss Induced by Restricted Energy Supply

Four male wistar rats having a mean body weight of 329±7 g were fed anexperimental diet provided as a mix of creamy, paste-like texture forfive days. The experimental diet was a high-fat chow compositioncomprising 50% fat relative to the final mixture, which was prepared byblending three standard chow diets as obtained from Ssniff®, namely ‘EFR/M Control, 5%’, ‘EF R/M with 30% fat’ and ‘EF R/M with 80% fat’, in aweight ratio of 10:45:45, respectively.

Chow supply was limited to 10 g per day representing a meanmetabolisable energy intake of 236 KJ per day. At the end of theexperiment, body weight change was evaluated (±SD). Animals lost3.6±0.6% body weight.

E. Pellet Chow Composition with 4.5% Fat and 9.1% Polymers—Example forPolymer-Induced Weight Loss Due to Reduced Uptake

Six male wistar rats having a mean body weight of 301.4±9.2 g were fedan experimental diet provided as pellets for seven days. The mixture wascomposed of standard chow diet (Ssniff® EF R/M Control, 5%) and in total10% polymers (relative to the standard chow weight; specifically 6.2%Carbopol® 971 NF, 1.5% Kollicoat® MAE 100P, Sigma-Aldrich, USA, and 2.3%chitosan from crab shells, Sigma-Aldrich, USA). This resulted in apellet chow composition with approx. 4.5% fat and approx. 9.1% totalpolymers relative to the final mixture (specifically, approx. 5.6%Carbopol®, approx. 1.4% Kollicoat® and approx. 2.1% chitosan).

Standard chow was mixed with polymer powders. Water was added to producea paste which was extruded and cut into pellets (1 cm×3 cm) by means ofa food processor (Kitchen Aid, USA). Pellets were dried at 25° C. overnight.

At the end of the experiment, food intake, energy intake and body weightchange were evaluated (±SD). Animals lost 3.9±4.6% body weight, meandaily food intake was 18.1±2.1 g, representing a mean metabolisableenergy intake of 253±29 kJ per animal per day.

F. Pellet Chow Composition with 4.7% Fat and 5.7% Polymer—Example forPolymer-Induced Weight Loss Due to Reduced Uptake

Six male wistar rats having a mean body weight of 317±14.5 g were fed anexperimental diet provided as pellets for seven days. The mixture wascomposed of standard chow diet (Ssniff® EF R/M Control, 5%) and 6%Carbopol® 971 NF (relative to the standard chow weight), resulting in apellet chow composition with approx. 4.7% fat and approx. 5.7% Carbopol®relative to the final mixture.

Standard chow was mixed with polymer powder, water was added to producea paste which was extruded and cut into pellets (1 cm×3 cm) by means ofa food processor (Kitchen Aid, USA). Pellets were dried at 25° C. overnight.

At the end of the experiment, food intake, energy intake and body weightchange were calculated (±SD). Animals lost 1.8±2.3% body weight, meandaily food intake was 18.4±5.3 g, representing a mean metabolisableenergy intake of 267±77 kJ per animal per day.

G. Powdered Pellet Chow/Witepsol® Composition with 11.0% Fat and 5.3%Polymer—Example for Polymer-Induced Weight Loss Due to Reduced Uptake

Six male wistar rats having a mean body weight of 307±8 g were fed anexperimental diet provided as powder for five days. The mixture wascomposed of standard chow diet (Ssniff® EF R/M Control, 5%) andWitepsol® W25 (7.5% relative to standard chow weight) and 6% Carbopol®971 NF (relative to standard chow weight), resulting in approx. 11.0%fat in total (including Witepsol®), approx. 6.6% Witepsol® and approx.5.3% Carbopol® relative to the final mixture.

Molten Witepsol® was mixed with polymer powder, transferred into azip-loc-bag and cooled to −18° C. in a freezer. The material was crushedby means of a hammer and shredded to a granulate in a kitchen blender(ProfiMIXX, Bosch, Germany). Standard chow diet was added and mixed withthe granulate to obtain a powder diet.

At the end of the experiment, food intake, energy intake and body weightchange were calculated (SD). Animals lost 2.4±1.8% body weight, meandaily food intake was 15.1±0.8 g, representing a mean metabolisableenergy intake of 245±13 kJ per animal per day.

Example 23: Breath Tests on Healthy Volunteers

Gastrointestinal half-life and bioavailability of free fatty acids wereassessed using the ¹³C-octanoic acid breath test. The labelled octanoicacid substrate is rapidly absorbed in the intestine and metabolised inthe liver with the production of ¹³CO₂, which is exhaled, thusreflecting uptake of octanoic acid from the gastrointestinal tract andafter exit from the stomach. At the beginning of the experiment areference breath sample was taken from the subject. Subsequently, thesubject consumed a load of either lipid granulate as reference sample,or lipid granulate containing polymers as test sample.

Granulate was prepared by melting lipid at 50° C. and adding 100 mg of¹³C octanoic acid (Campro Scientific, The Netherlands), and—for testsamples—incorporating polymer. The mixture was subsequently transferredinto a zip-loc-bag and cooled to −18° C. in a freezer. The material wascrushed by means of a hammer, shredded to a granulate in a kitchenblender (Bosch, Germany), dried under vacuum at 25° C. and classifiedthrough a set of wire mesh sieves (VWR International, Germany) to agranulate size of below 1.3 mm and above 0.5 mm.

For sample ingestion, frozen granulate was mixed with 100 g cold yogurt(fruit flavour, ca. 100 calories) and consumed within one to twominutes. After ingesting the samples, subject exhaled through amouthpiece to collect an end-expiratory breath sample into a 300 mL foilbag at time intervals. Breath samples were taken over a period of 410min. During this time period, 0.5-1.0 L of water were drunk at a rate ofapproximately one glass per hour, a light lunch was consumed after 180min, and physical exercise represented daily routine.

After completion of breath bag collection, analysis was performed bymeans of a FANci2 breath test analyser based on non-dispersive infraredspectroscopy (Fischer Analysen Instrumente GmbH, Germany). ¹³C abundancein breath was expressed as relative difference (‰) from the universalreference standard (carbon from Pee Dee Belemnite limestone). ¹³Cenrichment was defined as the difference between ¹³C abundance in breathprior to sample ingestion and ¹³C abundance at the defined time pointsafter sample ingestion and was given in delta over basal (DOB, ‰). Fromthe breath test analyser's operating software (FANci version 2.12.42.1402/14), values of cumulated percent dose rate (cPDR, corresponding tobioavailability), and the time at half the cPDR value (HLF,corresponding to gastrointestinal half-life) were taken to protocol.

Several test compositions with particles according to the invention wereadministered. As shown in the table below, it was found that theparticles lead to an increase in bioavailability (test compositions 1,2, 4, 5 and 6) or to an increased gastrointestinal half-time (testcomposition 3).

Hard fat (Witepsol®) was from NRC, Germany. Cocoa butter was purchasedat a local grocery store. Sodium laurate and lauric acid,microcrystalline cellulose and HPC qualities were from Sigma-Aldrich,USA. HPMC (Metolose® 90SH) was from Harke, Germany, Xanthan (XantanTexturas) was from Solegraells Guzman, Spain. Carbopol® was fromLubrizol, USA. Glycerolmonooleate and glycerolmonolaurate were from TCI,Belgium.

cPDR HLF Sample Lipid (g) Polymer (g) (%) (min) Reference 1 Cocoabutter: 6 g — 37 219 Reference 2 Witepsol W25: 6 g — 32 189 Reference 3Witepsol W25: 4 g — 32 180 sodium laurate: 1.25 g Reference 4 WitepsolW25: 2 g — 41 232 lauric acid: 2 g Reference 5 Prifex 300, 6 g — 29.091.5 Test com- Cocoa butter: 6 g Carbopol 971: 2 g 59 222 position 1Test com- Witepsol W25: 6 g HPC 1 MDa: 2 g 53 176 position 2 Test com-Witepsol W25: 4 g HPC 370 kDa: 1 39 243 position 3 sodium laurate: 1.25g g Test com- Witepsol W25: 2 g HPC 1 MDa: 2 g 57 172 position 4 lauricacid: 2 g Test com- Glycerolmonooleate: 3 g, HPMC: 1.3 g 59 165 position5 glycerolmonolaurate: 3 g Xanthan: 0.7 g Test com- Prifex 300, 5.5 gAlginex: 3 g 42.1 65.2 position 6 Aglupectin HS- RVP: 1 g PromOat: 1 g

Example 24: In Vitro Mucoadhesion and Particle Integrity Assay

Sodium alginate medium viscosity (alginate#1), alginic acid, sodiumlaurate and lauric acid, microcrystalline cellulose (MCC),hydroxypropyl-cellulose (HPC) and carboxymethyl-cellulose (CMC)qualities, gum arabic, chitosan and calcium salts were fromSigma-Aldrich, USA. Alginate#3 was from Dragonspice, Germany. Alginate#4(Satialgine® S 1600) was from Cargill, France. Alginate#5 (Manucol® DH)was from IMCD, Germany. Alginate#6 (Protanal® LF) and alginate#7(Protanal® PH) were from FMC, UK. Alginate#8 (Alginex® HH) andAlginate#9 (Algin LZ-2) were from Kimica, Japan. Carbopol® qualitieswere from Lubrizol, USA. Xanthan (Texturas Xantan), gellan gum (Texturasgellan), alginate#2 (Texturas Algin) were from Solegraells Guzman,Spain. HPMC (Metolose® 90SH) was from Harke, Germany. Psyllium qualities(99%; 100 Mesh) and guar gum were from Caremoli, Germany. Carob bean gumwas from Werz, Germany. Coconut flour was from Noble House, Belgium.Apple pectin, apple pectin low esterified and lysolecithin were fromDragonspice, Germany. Pectin#1 (Pektin Classic AU202) was fromHerbstreith & Fox, Germany. Pectin#2 (Aglupectin® HS-RVP) and Tara gum(AgluMix® 01) were from Silva Extracts, Italy. Low methoxyl pectin,amidated low methoxyl pectin, rapid set high methoxyl pectin, and slowset high methoxyl pectin qualities were from Modernist Pantry, USA.Beta-glucan (powder fill of Hafer-Beta glucan Bio Kapseln) was from RaabVitalfood, Germany. PromOat® beta-glucan was from Tate & Lyle, Sweden.Cocoa powder low fat was from Naturata, Germany. Cocoa powder high fatwas from Cebe, Germany. Inulin was from Spinnrad, Germany. Benefiber®resistant dextrin (also known as Benefiber® Nutriose®) was fromNovartis, UK.

Witepsol® hard fat qualities were from NRC, Germany. Gelucire® 43/01hard fat was from Gattefossé, France. Monoglycerides were from TCI,Belgium. Cocoa butter was purchased at a local super market. Palm fatwas from Peter Kölln, Germany. Palm stearin, Omega-3-Concentrate oil andOmega-3-Concentrate powder 67 were from Bressmer, Germany. Palm stearinIP and palm stearin MB were from Henry Lamotte, Germany. Coconut oil andcoconut fat qualities were from Dr. Goerg, Germany. Shea butter#1 wasfrom Gustav Hees, Germany. Shea butter#2 was from Cremer Oleo, Germany.Soy lecithin#1 (powder quality) was from Caelo, Germany. Soy lecithin#2(Texturas Lecite) was from Solegraells Guzman, Spain. Cocoa mass wasfrom Homborg, Germany. Cera flava and alba beeswax were from HeinrichKlenk, Germany. Conjugated linoleic acid (Tonalin®) was from BASF,Germany. Prifex® 300 palm stearin was from Unimills, The Netherlands.Omega-3 fatty acids (Omega-3 1400) were from Queisser Pharma, Germany.Safflower oil was from Brökelmann, Germany.

Granules were prepared by melting one lipid at 50° C. and optionallyadding other lipid components and a few crystals of Oil Red O (SigmaAldrich, USA) to obtain a homogenous melt or suspension. For testsamples polymer(s) were incorporated by mechanical mixing. Eachcomposition was transferred into a zip-loc-bag and cooled to −18° C. ina freezer. The material was first crushed by means of a hammer, shreddedto a granulate in a kitchen blender (Bosch ProfiMIXX, Germany),optionally dried under vacuum at 25° C. and then classified through aset of wire mesh sieves (VWR International, Germany) to a granulate sizeof below 2.0 mm and above 1.3 mm. Fresh pork stomach (from a localbutcher) was cut into 3 cm×3 cm pieces and placed into the bottom of aglass petri dish (10 cm diameter). 22 mL fasted-state simulated gastricfluid (FaSSGF) were added to the petri dish. FaSSGF was prepared bydis-solving 1 g of NaCl (Sigma-Aldrich) in 450 mL of water, adding 30 mgof SIF powder (biorelevant.com), adjusting the pH to 2.0 with 0.1 N HCl(Sigma-Aldrich) and adding water to a final volume of 500 mL. The petridish was covered and placed onto a petri dish shaker (ST5 from CAT,Germany) set to a tilt angle of 12° and a speed of 50/min. The shakerwas placed into an oven heated to a temperature of 37° C. After 30minutes, 350 mg granulate were added to the contents of the petri dishwithout interrupting agitation. After 5 min, the samples were removedfrom the oven, and the piece of pork stomach was rinsed three times withwater (3 mL each). The material bound to the stomach surface was removedby means of a spatula, transferred into a weighing dish, and dried toconstant weight (electronic moisture meter MLB 50-3N, Kern & Sohn,Germany). Dry weight of the mucoadhesive material was recorded andcalculated as percent of initial granulate weight, representing bindingas a measure of mucoadhesiveness. The petri dish containing theremaining unbound material was agitated at 37° C. for another 15 min,and particle integrity was classified by visual inspection as “low”(complete disintegration or disintegration of at least 50% of theparticles), or “high” (disintegration of less than 50% of the particles)or “medium” (disintegration of less than 50% of the particles, butvisible loss of small amounts of powders from the particles).

In result, it was found that certain test compositions with particlesaccording to the invention showed a substantially increased binding tothe mucosa and/or high particle integrity, as shown in the table below.

Particle Sample Lipid (g) Polymer (g) Binding integrity Test 1 WitepsolW25, 4 g HPC 1 MDa, 2 g 75% high Test 2 Witepsol W25, 4 g HPC 1 MDa, 1 g69% high CMC ultra high viscosity, 1 g Test 3 Witepsol W25, 4 g CMCultra high viscosity, 2 g 53% high Test 4 Cocoa butter, 2 g HPC, 1 g 91%high Lauric acid, 2 g CMC, 1 g Test 5 Cocoa butter, 2 g Carbopol 971, 2g 92% high Glycerolmonolaurate, 2 g Test 6 Cocoa butter, 2 g Carbopol971, 2 g 64% high Glycerolmonostearate, 2 g Test 7 Cocoa butter, 4 gHPC, 1 g 35% n.d. CMC, 1 g Test 8 Cocoa butter, 4 g HPC, 1 g 69% highCarbopol 971, 1 g Test 9 Cocoa butter, 4 g Carbopol 971, 2 g 77% highTest 10 Cocoa butter, 2 g Carbopol 971, 2 g 49% n.d. Lauric acid, 2 gTest 11 Cocoa butter, 4 g HPC 1 MDa, 2 g 44% n.d. Test 12 Cocoa butter,2 g HPC 1 MDa, 2 g 55% n.d. Glycerolmonolaurate, 2 g Test 13 Cocoabutter, 2 g HPC 1 MDa, 2 g 84% high Glycerolmonostearate, 2 g Test 14Glycerolmonooleate, 2 g HPMC, 2 g 50% n.d. Lauric acid, 2 g Test 15Glycerolmonooleate, 2 g HPMC, 2 g 52% n.d. Glycerolmonolaurate, 2 g Test16 Glycerolmonooleate, 2 g HPMC, 2 g 67% high Witepsol W25, 2 g Test 17Glycerolmonooleate, 3 g Carbopol 971, 2 g 81% high Glycerolmonolaurate,3 g Test 18 Glycerolmonooleate, 3 g HPMC, 1.3 g 72% highGlycerolmonolaurate, 3 g Xanthan, 0.7 g Test 19 Glycerolmonolaurate, 1.9g HPMC, 1.9 g 78% high Glycerolmonooleate, 1.1 g Xanthan, 0.1 g WitepsolW25, 1 g Test 20 Lauric acid, 4 g HPMC, 1.9 g 60% high Xanthan, 0.1 gTest 21 Lauric acid, 1.9 g HPMC, 1.9 g 75% high Glycerolmonooleate, 1.1g Xanthan, 0.1 g Witepsol W25, 1 g Test 22 Lauric acid, 1.9 g HPMC, 1.9g 73% high Glycerolmonooleate, 1.1 g Xanthan, 0.1 g Test 23Glycerolmonooleate, 2.05 g HPMC, 1.9 g 57% Witepsol W25, 1.95 g Xanthan,0.1 g Test 24 Glycerolmonolaurate, 1.9 g HPMC#2, 1.9 g 85% highGlycerolmonooleate, 1.1 g Xanthan, 0.1 g Medium chain triglycerides(MCT), 0.55 g Witepsol W25, 0.45 g Test 25 Glycerolmonolaurate, 1.35 gBeta-glucan, 1.95 g 68% high Glycerolmonooleate, 1.1 g HPMC, 1.6 g MCT,0.55 g Xanthan, 0.1 g Witepsol W25, 1 g Test 26 Glycerolmonolaurate, 1.9g HPMC, 2.4 g 75% high Glycerolmonooleate, 0.6 g Xanthan, 0.1 gGlycerol, 0.5 g Witepsol W25, 1 g Test 27 Glycerolmonolaurate, 1.35 gChitosan, 0.5 g 66% high Glycerolmonooleate, 1.1 g HPMC, 2.5 g MCT, 0.55g Xanthan, 0.1 g Witepsol W25, 1 g Test 28 Glycerolmonolaurate, 1.35 gBeta-glucan, 1.9 g 68% high Glycerolmonooleate, 1.1 g HPMC, 2.5 g MCT,0.55 g Xanthan, 0.1 g Witepsol W25, 1 g Test 29 Glycerolmonolaurate, 1.9g HPMC, 2.4 g 75% high Glycerolmonooleate, 0.6 g Xanthan, 0.1 gGlycerol, 0.5 g Witepsol W25, 1 g Test 30 Glycerolmonolaurate, 1.9 gHPMC, 1.9 g 43% high Glycerol, 0.5 g Xanthan, 0.1 g Witepsol W25, 1 gTest 31 Glycerolmonolaurate, 1.9 g HPMC, 2.5 g 26% high Glycerol, 1 gXanthan, 0.1 g Witepsol W25, 1 g Test 32 Glycerolmonolaurate, 1.9 gHPMC, 3.15 g 85% high Glycerolmonooleate, 1.1 g Xanthan, 0.1 g MCT, 0.55g Witepsol W25, 1 g Test 33 Glycerolmonolaurate, 1.9 g HPMC, 3.15 g 90%high Imwitor 990, 1.1 g Xanthan, 0.1 g MCT, 0.55 g Witepsol W25, 1 gTest 34 Glycerolmonolaurate, 1.35 g, HPMC, 2.8 g 81% high Imwitor 990,1.1 g, Xanthan, 0.1 g MCT, 0.55 g Witepsol W25, 1 g Test 35Glycerolmonolaurate, 1.35 g Chitosan, 0.5 g 66% high Glycerolmonooleate,1.1 g HPMC, 2.5 g MCT, 0.55 g Xanthan, 0.1 g Witepsol W25, 1 g Test 36Glycerolmonolaurate, 1.35 g PromOat, 1.9 g 61% high Glycerolmonooleate,1.1 g HPMC, 1.6 g MCT, 0.55 g Xanthan, 0.1 g Witepsol W25, 1 g Test 37Glycerolmonolaurate, 1.35 g PromOat, 2.5 g 68% high Glycerolmonooleate,1.1 g HPMC, 1 g MCT, 0.55 g Xanthan, 0.5 g Witepsol W25, 1 g Test 38Glycerolmonolaurate, 1.95 g PromOat, 1.5 g 90% high Imwitor 990, 1.6 gHPMC, 2.75 g MCT, 0.8 g Xanthan, 0.15 g Witepsol W25, 1.45 g Test 39Glycerolmonolaurate, 1.9 g HPMC, 1.9 g 83% high Imwitor 990, 1.1 gXanthan, 0.1 g Witepsol W25, 1 g Test 40 Glycerolmonolaurate, 3.2 gPromOat, 1.5 g 87% high Glycerolmonooleate, 1.8 g HPMC, 2.33 g WitepsolW25, 1.7 g Xanthan, 0.17 g Test 41 Glycerolmonolaurate, 3.2 g PromOat,1.5 g 65% high Imwitor 990, 1.8 g HPMC, 2.33 g Witepsol W25, 1.7 gXanthan, 0.17 g Test 42 Glycerolmonolaurate, 1.9 g HPMC, 2.5 g 85% highImwitor 990, 1.1 g Xanthan, 0.1 g Witepsol W25, 1 g Test 43Glycerolmonolaurate, 2.4 g PromOat, 1.5 g 86% high Glycerolmonooleate,1.3 g HPMC, 4 g Witepsol W25, 3.7 g Xanthan, 0.1 g Test 44Glycerolmonolaurate, 2.4 g PromOat, 3 g 83% high Glycerolmonooleate, 1.3g HPMC, 3 g Witepsol W25, 3.7 g Xanthan, 0.1 g Test 45Glycerolmonolaurate, 1.9 g HPMC, 1.9 g 72% high Glycerolmonooleate, 1.1g Xanthan, 0.1 g Witepsol H35, 1 g Test 46 Glycerolmonolaurate, 1.6 gHPMC, 1.9 g 86% high Glycerolmonooleate, 1.4 g Xanthan, 0.1 g WitepsolH35, 1 g Test 47 Glycerolmonolaurate, 1.9 g HPMC, 2.5 g 87% highGlycerolmonooleate, 1.1 g Xanthan, 0.1 g Witepsol H35, 1 g Test 48Glycerolmonolaurate, 2.6 g PromOat, 1 g 80% high Glycerolmonooleate, 1.4g HPMC, 2.9 g Witepsol W25, 4 g Xanthan, 0.1 g Test 49 Witepsol W25, 4 gHPMC, 2 g 47% high Test 50 Glycerolmonolaurate, 4 g HPMC, 2 g 45% highTest 51 Glycerolmonolaurate, 2.6 g PromOat, 1 g 65% highGlycerolmonooleate, 1.4 g HPMC, 3 g Witepsol W25, 4 g Test 52Glycerolmonolaurate, 1.6 g HPMC, 1.9 g 80% high Xanthan, 0.1 g Test 53Glycerolmonolaurate, 3 g HPMC, 1.9 g 83% high Witepsol W25, 1 g Xanthan,0.1 g Test 54 Glycerolmonolaurate, 2 g HPMC, 1.9 g 75% high WitepsolW25, 2 g Xanthan, 0.1 g Test 55 Glycerolmonolaurate, 1 g HPMC, 1.9 g 77%high Witepsol W25, 3 g Xanthan, 0.1 g Test 56 Glycerolmonolaurate, 2 gHPMC, 2.85 g 78% high Witepsol W25, 4 g Xanthan, 0.15 g Test 57Glycerolmonolaurate, 4 g PromOat, 1 g 80% high Witepsol W25, 4 g HPMC,2.9 g Xanthan, 0.1 g Test 58 Glycerolmonolaurate, 3 g PromOat, 1.125 g70% high Witepsol W25, 6 g HPMC, 3.26 g Xanthan, 0.125 g Test 59Glycerolmonolaurate, 2 g PromOat, 1 g 95% high Witepsol W25, 6 g HPMC,2.9 g Xanthan, 0.1 g Test 60 Gelucire 43/01, 1 g HPMC, 1.9 g 81% highWitepsol W25, 3 g Xanthan, 0.1 g Test 61 Gelucire 43/01, 2 g HPMC, 2.85g 78% high Witepsol W25, 4 g Xanthan, 0.15 g Test 62 Gelucire 43/01, 3 gPromOat, 1.125 g 82% high Witepsol W25, 6 g HPMC, 3.26 g Xanthan, 0.125g Test 63 Gelucire 43/01, 2 g PromOat, 1 g 78% high Witepsol W25, 6 gHPMC, 2.9 g Xanthan, 0.1 g Test 64 Glycerolmonolaurate, 1 g HPMC, 2 g80% high Witepsol W25, 3 g Test 65 Glycerolmonolaurate, 2 g PromOat, 1 g82% high Witepsol W25, 6 g HPMC, 3 g Test 66 Glycerolmonolaurate, 2 gPsyllium (99%; 100 Mesh), 93% high Witepsol W25, 6 g 3 g HPMC, 1 g Test67 Glycerolmonolaurate, 2 g Psyllium (99%; 100 Mesh), 85% high WitepsolW25, 1 g 3 g Shea butter, 5 g HPMC, 1 g Test 68 Glycerolmonolaurate, 2 gPsyllium (99%; 100 Mesh), 60% high Witepsol W25, 2 g 3 g Shea butter, 4g HPMC, 1 g Test 69 Glycerolmonolaurate, 2 g PromOat, 1 g 90% highWitepsol W25, 6 g Apple pectin, 1 g HPMC, 2 g Test 70Glycerolmonolaurate, 2 g PromOat, 1 g 55% high Witepsol W25, 6 g Applepectin, 1 g HPMC, 1.9 g Xanthan, 0.1 g Test 71 Glycerolmonolaurate, 2 gPromOat, 0.5 g 80% high Witepsol W25, 6 g Apple pectin, 0.5 g HPMC, 3 gTest 72 Glycerolmonolaurate, 2 g PromOat, 0.5 g 65% high Witepsol W25, 6g Apple pectin, 1.5 g HPMC, 2 g Test 73 Glycerolmonolaurate, 2 gPromOat, 1.5 g 50% medium Witepsol W25, 6 g Apple pectin, 1.5 g HPMC, 1g Test 74 Witepsol W25, 2 g HPMC, 2 g 88% high Cocoa powder (high-fat),2 g Test 75 Glycerolmonolaurate, 2 g HPMC, 3 g 85% high Witepsol W25, 4g Cocoa powder (high-fat), 4 g Test 76 Glycerolmonolaurate, 2 g PromOat,1 g 45% medium Witepsol W25, 4 g HPMC, 2 g Cocoa powder (high-fat), 4 gTest 77 Gelucire 43/01, 2 g HPMC, 4 g 89% high Witepsol W25, 4 g Cocoapowder (high-fat), 4 g Test 78 Gelucire 43/01, 2 g Apple pectin, 1 g 77%high Witepsol W25, 4 g HPMC, 3 g Cocoa powder (high-fat), 4 g Test 79Gelucire 43/01, 2 g HPMC, 4 g 90% high Witepsol W25, 4 g Cocoa powder(low-fat), 4 g Test 80 Gelucire 43/01, 2 g HPMC, 3 g 70% high WitepsolW25, 4 g Xanthan, 1 g Cocoa powder (low-fat), 4 g Test 81 Gelucire43/01, 2 g Psyllium (99%; 100 Mesh), 75% high Witepsol W25, 4 g 2 gHPMC, 2 g Cocoa powder (low-fat), 4 g Test 82 Gelucire 43/01, 2 gPsyllium (99%; 100 Mesh), 25% high Witepsol W25, 4 g 1 g HPMC, 2 gXanthan, 1 g Cocoa powder (low-fat), 4 g Test 83 Gelucire 43/01, 2 gHPMC, 3.8 g 85% high Witepsol W25, 3.5 g Xanthan, 0.2 gGlycerolmonooleate, 0.5 g Cocoa powder (low-fat), 4 g Test 84 Gelucire43/01, 2 g Alginate 1, 2 g 57% high Witepsol W25, 4 g HPMC, 2 g Cocoapowder (low-fat), 4 g Test 85 Gelucire 43/01, 2 g PromOat, 0.5 g 71%high Witepsol W25, 4 g HPMC, 3.5 g Palm fat, 2 g Cocoa powder (low-fat),0.5 g Test 86 Gelucire 43/01, 2 g PromOat, 0.5 g 72% high Witepsol W25,4 g HPMC, 3.3 g Palm fat, 2 g Xanthan, 0.2 Test 87 Gelucire 43/01, 6 gPromOat, 0.5 g 92% high Palm fat, 2 g HPMC, 3.4 g Xanthan, 0.1 Test 88Glycerolmonolaurate, 1 g Alginate#1, 1 g 88% high Witepsol W25, 3 gHPMC, 1 g Test 89 Glycerolmonolaurate, 1.33 g Alginate#1, 1 g 60% highWitepsol W25, 1.33 g HPMC, 1 g Coco fat, 1.33 g Test 90Glycerolmonolaurate, 1.33 g Alginate#1, 1 g 80% high Witepsol W25, 1.33g HPMC, 1 g Coco oil, 1.33 g Test 91 Glycerolmonolaurate, 1.33 gAlginate#1, 1 g 84% high Witepsol W25, 1.33 g HPMC, 1 g Coco oil, 1.33 gCocoa powder (strong de- oiled), 1 g Test 92 Glycerolmonolaurate, 1.33 gAlginate#1, 1 g 86% high Witepsol W25, 1.33 g HPMC, 1 g Coco oil, 1.33 gCalcium L-lactate hydrate, 0.006 g Test 93 Glycerolmonolaurate, 1.33 gAlginate#1, 1 g 60% high Witepsol W25, 1.33 g HPMC, 1 g Coco oil, 1.33 gCalcium L-lactate hydrate, 0.06 g Test 94 Glycerolmonolaurate, 1.33 gAlginate#1, 1 g 49% high Witepsol W25, 1.33 g HPMC, 1 g Coco oil, 1.33 gCalcium L-lactate hydrate, 0.6 g Test 95 Glycerolmonolaurate, 2.67 gAlginate#1, 1 g 60% high Witepsol W25, 1.67 g HPMC, 1 g Coco oil, 1.67 gCocoa mass, 4 g Test 96 Glycerolmonolaurate, 1 g Alginate#2, 1 g 92%high Witepsol W25, 3 g HPMC, 1 g Test 97 Glycerolmonolaurate, 1 gAlginate#2, 1 g 62% high Witepsol W25, 3 g HPMC, 1 g Calcium L-lactatehydrate, 0.006 g Test 98 Glycerolmonolaurate, 1 g HPMC, 2 g 80% highWitepsol W25, 2.5 g Coco oil, 0.5 g Test 99 Witepsol W25, 4 g HPC 1.15MDa, 2 g 92% high Test 100 Witepsol W25, 4 g HPC 0.85 MDa, 2 g 92% highTest 101 Glycerolmonolaurate, 1 g Low methoxyl pectin, 2 g 45% mediumWitepsol W25, 3 g Test 102 Glycerolmonolaurate, 1 g Amidated lowmethoxyl 74% high Witepsol W25, 3 g pectin, 2 g Test 103Glycerolmonolaurate, 1 g Rapid set high methoxyl 62% high Witepsol W25,3 g pectin, 2 g Test 104 Glycerolmonolaurate, 1 g Slow set high methoxyl81% high Witepsol W25, 3 g pectin, 2 g Test 105 Glycerolmonolaurate, 1 gSlow set high methoxyl 85% high Witepsol W25, 3 g pectin, 4 g Test 106Glycerolmonolaurate, 1 g Apple pectin, 2 g 66% high Witepsol W25, 3 gTest 107 Glycerolmonolaurate, 1 g Apple pectin, 4 g 90% high WitepsolW25, 3 g Test 108 Glycerolmonolaurate, 2 g Apple pectin, 3 g 70% highWitepsol W25, 4 g Test 109 Glycerolmonolaurate, 2 g Apple pectin, 4 g86% high Witepsol W25, 4 g Test 1102 Glycerolmonolaurate, 1 g Xanthan, 2g 73% high Witepsol W25, 3 g Test 111 Glycerolmonolaurate, 1 g Xanthan,1 g 65% high Witepsol W25, 3 g Test 112 Glycerolmonolaurate, 1 g Carobbean gum, 2 g 46% medium Witepsol W25, 3 g Test 113 Glycerolmonolaurate,1 g PromOat, 1 g 63% high Witepsol W25, 3 g Xanthan, 1 g Test 114Glycerolmonolaurate, 1 g Psyllium (95%; 40 Mesh), 3 g 68% high WitepsolW25, 3 g Test 115 Glycerolmonolaurate, 1 g Psyllium (98%; 100 Mesh), 46%medium Witepsol W25, 3 g 3 g Test 116 Glycerolmonolaurate, 1 g Psyllium(99%; 100 Mesh), 85% high Witepsol W25, 3 g 3 g Test 117Glycerolmonolaurate, 1 g Psyllium (99%; 100 Mesh 70% high Witepsol W25,3 g Plus), 3 g Test 118 Glycerolmonolaurate, 1 g Psyllium (99%; 100Mesh), 52% medium Witepsol W25, 3 g 2 g Test 119 Glycerolmonolaurate, 1g Psyllium (99%; 100 Mesh), 70% high Witocan H, 3 g 3 g Test 120Glycerolmonolaurate, 1 g Psyllium (99%; 100 Mesh), 60% high Witocan P, 3g 3 g Test 121 Glycerolmonolaurate, 2 g Psyllium (99%; 100 Mesh), 50%medium Shea butter 1.2 g 3 g Test 122 Glycerolmonolaurate, 2 g Psyllium(99%; 100 Mesh), 42% medium Shea butter 2.2 g 3 g Test 123Glycerolmonolaurate, 1 g Guar gum (200 Mesh), 2 g 26% low Witepsol W25,3 g Test 124 Glycerolmonolaurate, 1 g Carbopol 971, 2 g 84% highWitepsol W25, 3 g Test 125 Glycerolmonolaurate, 1 g Alginic acid, 2 g15% low Witepsol W25, 3 g Test 126 Glycerolmonolaurate, 1 g Alginate#2,2 g 86% high Witepsol W25, 3 g Test 127 Glycerolmonolaurate, 1 gAlginate#2, 1 g 95% high Witepsol W25, 3 g Apple pectin, 1 g Test 128Glycerolmonolaurate, 1 g Alginate#2, 1 g 80% high Witepsol W25, 3 gPrickly pear pectin, 1 g Test 129 Cera flava, 3.2 g Alginate#2, 2 g 85%high Coco oil, 4.8 g Apple pectin, 2 g Test 130 Cera alba, 3.2 gAlginate#2, 2 g 84% high Coco oil, 4.8 g Apple pectin, 2 g Test 131Gelucire 43/01, 6 g Alginate#2, 2 g 59% high Coco oil, 2 g Apple pectin,1.9 g Konjac flour, 0.1 g Test 132 Gelucire 43/01, 6 g Alginate#2, 2 g75% high Coco oil, 2 g Apple pectin, 1.9 g Xanthan, 0.1 g Test 133Glycerolmonolaurate, 1 g Alginate#3, 2 g 75% high Witepsol W25, 3 g Test134 Glycerolmonolaurate, 1 g Alginate#2, 2 g 68% high Witepsol W25, 3 gAmidated low methoxyl pectin, 2 g Test 135 Glycerolmonolaurate, 1 gAlginate#2, 2 g 75% high Witepsol W25, 3 g Low methoxyl pectin, 2 g Test136 Glycerolmonolaurate, 1 g Alginate#2, 2 g 65% high Witepsol W25, 3 gSlow set high methoxyl pectin, 2 g Test 137 Glycerolmonolaurate, 1 gAlginate#2, 2 g 78% high Witepsol W25, 3 g Rapid set high methoxylpectin, 2 g Test 138 Gelucire 43/01, 4 g Alginate#2, 2 g 91% high Cocooil, 2 g Apple pectin, 2 g Soy lecithin #1, 2 g Test 139 Gelucire 43/01,5 g Alginate#2, 2 g 92% high Coco oil, 2 g Apple pectin, 2 g Soylecithin #1, 1 g Test 140 Gelucire 43/01, 5 g Alginate#2, 2 g 86% highCoco oil, 2 g Apple pectin, 2 g Soy lecithin #2, 1 g Test 141 Witocan P,4 g MCC, 2 g <2% low Test 142 Witepsol W25, 4 g MCC, 2 g <2% low Test143 Palm stearin, 7 g Alginate#2, 2 g 93% high Soy lecithin #1, 1 gApple pectin, 2 g Test 144 Palm stearin, 8 g Alginate#2, 2 g 70% highApple pectin, 2 g PromOat, 2 g Cocoa powder (low fat), 2 g Test 145 Palmstearin, 8 g Alginate#2, 2 g 55% high Apple pectin, 2 g Test 146 Palmstearin, 7 g Alginate#2, 2 g 56% high Soy lecithin #1, 1 g Apple pectin,2 g PromOat, 2 g Test 147 Palm stearin, 7 g Alginate#2, 2 g 48% high Soylecithin #1, 1 g Apple pectin, 2 g Cocoa powder (low fat), 2 g Test 148Palm stearin, 7 g Alginate#2, 2 g 50% high Soy lecithin #1, 1 g Applepectin, 2 g Psyllium, 2 g Test 149 Palm stearin, 7 g Alginate#2, 2 g 62%high Soy lecithin #1, 1 g Apple pectin, 2 g Coco flour, 2 g Test 150Palm stearin, 7 g Alginate#2, 4 g 70% high Soy lecithin #1, 1 g Applepectin, 4 g Test 151 Glycerolmonolaurate, 4 g Alginate#2, 2 g 65% highCoco oil, 4 g Apple pectin, 2 g Test 152 Glycerolmonolaurate, 3 gAlginate#2, 2 g 65% high Palm stearin, 1 g Apple pectin, 2 g Coco oil, 4g Test 153 Glycerolmonolaurate, 2.67 g Alginate#2, 2 g 67% high Palmstearin, 2.67 g Apple pectin, 2 g Coco oil, 2.67 g Test 154Glycerolmonolaurate, 3.5 g Alginate#2, 2 g 87% high Coco oil, 3.5 gApple pectin, 2 g Soy lecithin #2, 1 g Test 155 Glycerolmonolaurate, 3 gAlginate#2, 2 g 92% high Palm stearin, 1 g Apple pectin, 2 g Coco oil, 3g Soy lecithin #2, 1 g Test 156 Palm stearin, 7 g Alginate#2, 4 g 65%high Soy lecithin #1, 1 g Test 157 Palm stearin, 7 g Alginate#2, 2 g 84%high Soy lecithin #1, 1 g Apple pectin, 2 g Gum arabic, 1 g Test 1598Palm stearin, 7 g Alginate#2, 2.7 g 91% high Soy lecithin #1, 1 g Applepectin, 1.3 g Test 159 Palm stearin, 7 g Alginate#2, 1.3 g 50% high Soylecithin #1, 1 g Apple pectin, 2.7 g Test 160 Palm stearin, 6 gAlginate#2, 2 g 83% high Cera flava, 1 g Apple pectin, 2 g Soy lecithin#1, 1 g Test 161 Palm stearin, 7 g Alginate#2, 2.7 g 85% high Soylecithin #1, 1 g Apple pectin, 1.3 g Calcium carbonate, 0.012 g Test 162Palm stearin, 7 g Alginate#2, 2.7 g 77% high Soy lecithin #1, 1 g Applepectin, 1.3 g Calcium carbonate, 0.12 g Test 163 Palm stearin MB, 7 gAlginate#2, 2.7 g 69% high Soy lecithin #1, 1 g Apple pectin, 1.3 g Test164 Palm stearin IP, 7 g Alginate#2, 2.7 g 45% high Soy lecithin #1, 1 gApple pectin, 1.3 g Test 165 Palm stearin, 7 g Alginate#2, 2.7 g 92%high Soy lecithin #2, 1 g Apple pectin, 1.3 g Test 166 Palm stearin, 7.5g Alginate#2, 2.7 g 63% high Soy lecithin #2, 0.5 g Apple pectin, 1.3 gTest 167 Palm stearin, 6.5 g Alginate#2, 2.7 g 70% high Soy lecithin #2,1.5 g Apple pectin, 1.3 g Test 168 Palm stearin, 6.5 g Alginate#2, 2.7 g80% high Soy lecithin #1, 1.5 g Apple pectin, 1.3 g Inulin, 1 g Test 169Palm stearin, 6.5 g Alginate#2, 2.7 g 65% high Soy lecithin #1, 1.5 gApple pectin (low esterified), 1.3 g Test 170 Palm stearin, 7 gAlginate#2, 2.7 g 70% high Lysolecithin 1, 1 g Apple pectin, 1.3 g Test171 Palm stearin, 4 g Alginate#2, 10 g 75% high Soy lecithin #2, 1 gTest 172 Palm stearin, 6.5 g Alginate#2, 7.5 g 85% high Soy lecithin #2,1 g Test 173 Palm stearin, 6.5 g Alginate#2, 5 g 70% high Soy lecithin#2, 1 g Apple pectin, 2.5 g Test 174 Palm stearin, 6.5 g Alginate#2,3.75 g 59% high Soy lecithin #2, 1 g Apple pectin, 3.75 g Test 175 Palmstearin, 6.5 g Alginate#4, 7.5 g 80% high Soy lecithin #2, 1 g Test 176Palm stearin, 6.5 g Alginate#4, 5 g 82% high Soy lecithin #2, 1 g Applepectin, 2.5 g Test 177 Palm stearin, 6.5 g Alginate#4, 3.75 g 82% highSoy lecithin #2, 1 g Apple pectin, 3.75 g Test 178 Palm stearin, 7.5 gAlginate#4, 7.5 g 60% high Test 179 Palm stearin, 4 g Alginate#4, 10 g76% high Soy lecithin #2, 1 g Test 180 Palm stearin, 4 g Alginate#4, 7.5g 85% high Soy lecithin #2, 1 g Test 181 Palm stearin, 6.5 g Alginate#4,3.75 g 73% high Soy lecithin #2, 1 g Pectin#1, 3.75 g Test 182 Palmstearin, 5 g Alginate#4, 7.5 g 73% high Test 183 Palm stearin, 4.75 gAlginate#4, 7.5 g 74% high Soy lecithin #2, 0.25 g Test 184 Palmstearin, 4.5 g Alginate#4, 7.5 g 79% high Soy lecithin #2, 0.5 g Test185 Palm stearin, 5 g Alginate#5, 7.5 g 68% high Test 186 Palm stearin,5 g Alginate#6, 7.5 g 51% high Test 187 Palm stearin, 5 g Alginate#7,7.5 g 32% Test 188 Palm stearin, 5 g Alginate#8, 7.5 g 72% high Test 189Palm stearin, 5 g Alginate#9, 7.5 g 31% high Test 190 Palm stearin, 8 gAlginate#7, 4 g 19% medium Test 191 Palm stearin, 8 g Alginate#8, 4 g73% high Test 192 Palm stearin, 8 g Alginate#9, 4 g 13% medium Test 193Palm stearin, 7.5 g Alginate#8, 5 g 75% yes Test 194 Palm stearin, 6 gAlginate#8, 6 g 78% no Test 195 Palm stearin, 6 g Alginate#8, 5 g 76%yes Pectin#1, 1 g Test 196 Palm stearin, 6 g Alginate#8, 5 g 82% highPectin#2, 1 g Test 197 Palm stearin, 6 g Alginate#4, 5 g 82% highPectin#2, 1 g Test 198 Palm stearin, 6 g Alginate#4, 5 g 75% highPectin#2, 1 g PromOat, 1 g Test 199 Palm stearin, 6 g Alginate#4, 5 g83% high Pectin#2, 1 g PromOat, 0.5 g Test 200 Palm stearin, 6 gAlginate#4, 4 g 85% high Pectin#2, 1 g PromOat, 1 g Test 201 Palmstearin, 6 g Alginate#4, 5 g 91% high PromOat, 1 g Test 202 Palmstearin, 6 g Alginate#4, 4 g 84% high PromOat, 2 g Test 203 Palmstearin, 7 g Alginate#4, 3 g 92% high Pectin#2, 1 g PromOat, 1 g Test204 Palm stearin, 7 g Alginate#8, 3 g 94% high Pectin 2, 1 g PromOat, 1g Test 205 Palm stearin, 6.5 g Alginate#4, 3 g 73% high Conjugatedlinoleic acid, Pectin#2, 1 g 0.5 g PromOat, 1 g Test 206 Palm stearin, 6g Alginate#4, 3 g 73% high Conjugated linoleic acid, 1 g Pectin#2, 1 gPromOat, 1 g Test 207 Glycerolmonolaurate, 1 g HPMC, 2 g 83% highWitepsol W25, 2.5 g Conjugated linoleic acid, 0.5 g Test 208 Palmstearin, 7 g Alginate#4, 3 g 89% high Apple pectin, 1 g PromOat, 1 gTest 209 Palm stearin, 5 g Alginate#4, 3 g 87% high Apple pectin, 1 gPromOat, 1 g Test 210 Palm stearin, 5 g Alginate#4, 3 g 89% high Pectin2, 1 g PromOat, 1 g Test 211 Palm stearin, 5.5 g Alginate#4, 3 g 89%high Apple pectin, 1 g PromOat, 1 g Test 212 Palm stearin, 6 gAlginate#4, 3 g 89% high Apple pectin, 1 g PromOat, 1 g Test 213 Palmstearin, 6 g, 3.8 g Alginate#4, 3 g 92% high Omega-3 fatty acid 1, 1.2 gApple pectin, 1 g PromOat, 1 g Test 214 Prifex 300, 5.5 g Alginate#4, 3g 86% high Apple pectin, 1 g PromOat, 1 g Test 215 Prifex 300, 5.5 gAlginate#4, 3 g 87% high Pectin 2, 1 g PromOat, 1 g Test 216 Palmstearin, 5.5 g Alginate#4, 3 g 76% high Benefiber, 2 g Test 217 Palmstearin, 5.5 g Alginate#4, 3 g 81% high Pectin 2, 1 g Benefiber, 1 gTest 218 Palm stearin, 5.5 g Alginate#4, 1 g 63% high Benefiber, 4 gTest 219 Palm stearin, 5.5 g Alginate#4, 2 g 82% high Benefiber, 3 gTest 220 Palm stearin, 5.5 g Alginate#4, 2.5 g 78% high Benefiber, 2.5 gTest 221 Palm stearin, 5.5 g Alginate#4, 2 g 82% high Benefiber, 3 gTest 222 Palm stearin, 5.5 g Alginate#4, 2.5 g 78% high Benefiber, 2.5 gTest 223 Palm stearin, 5 g Tara gum, 5 g 62% high Test 224 Palm stearin,5 g Gum arabic, 5 g n.d. high Test 225 Palm stearin, 5 g Pectin 2, 1 gn.d. medium Benefiber, 2 g PromOat, 2 g Test 226 Palm stearin, 5 gPectin 2, 1 g n.d. medium Benefiber, 2.5 g PromOat, 1.5 g Test 227Prifex 300, 3.5 g Alginate 8, 3 g 86% high Safflower oil, 2 g Pectin 2,1 g Omega-3 oil, 0.5 g Benefiber, 2 g Test 228 Prifex 300, 3.5 gAlginate 4, 3 g 77% high Safflower oil, 2 g Pectin 2, 1 g Omega-3 oil,0.5 g Benefiber, 2 g Test 229 Prifex 300, 3.5 g Alginate 8, 3 g 60% highSafflower oil, 2 g Pectin 2, 1 g Omega-3 oil, 0.5 g Benefiber, 3 g Test230 Prifex 300, 3.5 g Alginate 8, 3 g 71% high Safflower oil, 2 g Pectin2, 1 g Omega-3 oil, 0.5 g Benefiber, 3 g PromOat, 1.5 g Test 231 Prifex300, 3.5 g Alginate 8, 3 g 83% high Safflower oil, 2 g Pectin 2, 1 gOmega-3 oil, 0.5 g Nutriose FB, 2 g Test 232 Prifex 300, 3.5 g Alginate8, 3 g 82% high Safflower oil, 2 g Pectin 2, 1 g Omega-3 oil, 0.5 gNutriose FM, 2 g Test 233 Prifex 300, 9 g Alginate 8, 3 g 60% highLinseed oil, 1 g Pectin 2, 1 g PromOat, 1 g Benefiber, 5 g Test 234Prifex 300, 5.5 g Alginex, 3 g 83% high Aglupectin HS-RVP, 1 g PromOat 1g

Example 25: Preparation of a Premix by High-Shear Granulation

4.5 kg of hard fat (Witepsol® W25, Cremer Oleo), 1.5 kg of glycerolmonolaurate (Mosselman, Belgium), and 3.0 kg HPMC (Metolose 60SH, ShinEtsu, Japan) were introduced into a Ploughshare mixer (Lödige, Germany)equipped with a heating jacket. Under continuous mixing operation at 80rpm, the temperature in the vessel was raised to 60° C. and until thelipid components were completely molten. With continued mixing, heatingwas stopped and 2 kg of crushed dry ice were added within 5 min. Theresulting granulate was removed from the vessel after evaporation of thecarbon dioxide used as premix for extrusion experiments. Whereconsidered expedient, the resulting granulate particles were dried undervacuum at 25° C. to remove residual condensed water; e.g. prior toclassifying them.

Example 26: Preparation of a Premix by High-Shear Granulation

3.0 kg of hard fat (Witepsol® W25, Cremer Oleo), 1.0 kg of glycerolmonolaurate (Mosselman, Belgium) were introduced into a Ploughsharemixer (Lödige, Germany) equipped with a heating jacket. Under continuousmixing operation at 80 rpm, the temperature in the vessel was raised to60° C. and until the lipid components were completely molten. Withcontinued mixing, heating was stopped and 3.0 kg of psyllium seed husks(Carepsyllium, Caremoli, Germany) were added and after 5 min, 2 kg ofcrushed dry ice were added within 5 min. The resulting granulate wasremoved from the vessel after evaporation of the carbon dioxide and usedas premix for extrusion experiment 29. Where considered expedient, theresulting granulate particles were dried under vacuum at 25° C. toremove residual condensed water; e.g. prior to classifying them.

Example 27: Preparation of a Granulate by High-Shear Granulation

750 g of hard fat (Witepsol® W25, Cremer Oleo), 250 g of glycerolmonolaurate (Mosselman, Belgium), and 500 g HPMC (Metolose® 60SH, ShinEtsu, Japan) were introduced into a Ploughshare mixer (Lödige, Germany)equipped with a heating jacket. Under continuous mixing operation at 200rpm, the temperature in the vessel was raised to 54° C. and until thelipid components were completely molten. With continued mixing, heatingwas stopped and 1 kg of crushed dry ice was added within 5 min. Theresulting granulate was removed from the vessel, optionally dried undervacuum at 25° C. and passed through a set of wire mesh sieves (1.0 mm(mesh 18) and 2.0 mm (mesh 10) and 3.15 mm, VWR, Germany) to give theproduct. 51% (w/w) of the material were obtained as particle sizefraction of 1.0-3.15 mm.

Example 28: Preparation of a Granulate by High-Shear Granulation

900 g alginate (Satialgine®, Cargill, Germany), 60 g soy lecithin(powder quality, Golden Peanut, Germany) and 540 g of palm stearin (PalmStearin 54, Bressmer, Germany) were introduced into a Ploughshare mixer(Lödige, Germany) equipped with a heating jacket. Under continuousmixing operation at 200 rpm, the temperature in the vessel was raised to60° C. and until the lipid components were completely molten. Withcontinued mixing, heating was stopped and 440 g of crushed dry ice wereadded within 5 min. The resulting granulate was removed from the vessel,optionally dried under vacuum at 25° C. and passed through a set of wiremesh sieves (1.0 mm (mesh 18) and 2.0 mm (mesh 10) and 3.15 mm, VWR,Germany) to give the product. 48% (w/w) of the material were obtained asparticle size fraction of 1.0-3.15 mm.

Example 29: Preparation of Particles by Extrusion

A premix prepared according to the protocol of experiment 26, comprising300 g hard fat (Witepsol® W25, Cremer Oleo, Germany), 100 g glycerolmonolaurate (Mosselman, Belgium) and 300 g psyllium seed husks(Carepsyllium, Caremoli, Germany), was fed via a volumetric dosingsystem (Dosimex DO-50, Gabler, Germany) into a powder inlet of a twinscrew extruder (Extruder DE-40/10, Gabler, Germany) and extruded at atemperature range of 30-35° C. to strands of 1.0 mm diameter. Extrudedstrands were cut to granules by means of rotating blades. Granules weresubsequently rounded in a spheroniser (Spheronizer 250, Gabler, Germany)to particles of ca. 1 mm diameter.

Example 30: Preparation of Particles by Extrusion

A molten premix of 187.5 g hard fat (Witepsol® W25, Cremer Oleo,Germany), 356.25 g glycerol monolaurate (Mosselman, Belgium) and 206.25g glycerol monooleate (Mosselman, Belgium) was prepared in a beaker on ahot plate (at 80° C.) equipped with an overhead stirrer and was fed bymeans of a peristaltic pump (Masterflex®, Thermo Fisher, Germany) to oneinlet opening of a twin screw extruder (Pharma 11 HME, Thermo Fisher,Germany). In parallel, a powder premix of 256.25 g HPMC (Metolose® 60SH,Shin Etsu, Japan) and 18.75 g xanthan (Xanthan FF, Jungbunzlauer,Switzerland) were fed via volumetric dosing system (Volumetric SingleScrew Feeder, Thermo Fisher, Germany) to the powder inlet opening of theextruder, and the mixture was extruded at a temperature range of 30-35°C. to strands of 1.5 mm diameter and subsequently broken and rounded ina spheroniser (Caleva MBS 120, Thermo Fisher, Germany) to a granulate ofca. 1-2 mm.

Example 31: Coating of Cores with a Mixture of Lipid and Emulsifier

600 g granulate prepared according to one of examples 27-30 were loadedinto fluid bed device (Ventilus V-2.5/1, Innojet, Germany, equipped withan IPC3 product reservoir) and fluidised at a bed temperature of 20° C.at an air flow of 90 cubic meters/h. 105.0 g Dynasan® 115 and 45.0 gPolysorbate 65 were molten in a beaker on a hot plate (at 80° C.)equipped with an overhead stirrer. The hot melt was sprayed onto thegranulate using a peristaltic pump and a top spraying procedure at aspray rate of 6.5 g/min. Samples of different amounts of coating weretaken at time intervals, corresponding to 10, 15, 20, and 25% (w/w).

Example 32: Coating of Cores with a Mixture of Lipid and Hydrocolloid

600 g granulate prepared according to one of examples 27-30 were loadedinto fluid bed device (Ventilus V-2.5/1, Innojet, Germany, equipped withan IPC3 product reservoir) and fluidised at a bed temperature of 20° C.at an air flow of 90 cubic meters/h. 135 g Dynasan® 116 and 15 g guargum (Careguar, Caremoli, Germany) were heated on a hot plate (80° C.)equipped with a mechanical stirrer. The hot melt sprayed onto thegranulate using a peristaltic pump and a top spraying procedure at aspray rate of 6.5 g/min. Samples of different amounts of coating weretaken at time intervals, corresponding to 15 and 25% (w/w).

Example 33: Mucoadhesion Assay of Coated Granulate

Granulate prepared according to experiment 30 were coated according toexperimental procedure 31 to different coating thickness and subjectedto the mucoadhesion assay protocol described above, except that bindingkinetics were followed up to 30 min.

Pork stomach binding of the granulate sample carrying 10% (w/w) coatingwas maximal after 6 min. Pork stomach binding of the granulate samplecarrying 15% (w/w) coating was maximal after 9 min. Pork stomach bindingof the granulate sample carrying 20% (w/w) coating was maximal after 12min. Pork stomach binding of the granulate sample carrying 25% (w/w)coating was maximal after 25 min.

Example 34: Mucoadhesion Assay of Coated Granulate

Granulate prepared according to experiment 30 were coated according toexperimental procedure 32 to different coating thickness and subjectedto the mucoadhesion assay protocol described above, except that bindingkinetics were followed up to 30 min.

Pork stomach binding of the granulate sample carrying 15% (w/w) coatingwas maximal after 14 min. Pork stomach binding of the granulate samplecarrying 20% (w/w) coating was maximal after 25 min.

Example 35: Preparation of Granulate by Extrusion

A premix prepared according to the protocol of experiment 26, comprising224 g palm stearin (Palmstearin 54, Juchem, Germany), 96 g alginate(Satialgine®, Cargill, France), 32 g pectin (Aglupectin® HS-RVP,Silvateam, Italy) and 32 g oat beta glucan (PromOat®, Tate & Lyle,Sweden), was fed via a volumetric dosing system (Dosimex DO-50, Gabler,Germany) into a powder inlet of a twin screw extruder (ExtruderDE-40/10, Gabler, Germany, operating at 7 rpm) and extruded at atemperature range of 10-12° C. to strands of 1.5 mm diameter. Extrudedstrands were cut to granules of 0.8-2.5 mm length by means of rotatingblades (running at 100 rpm). The premix was quantitatively convertedinto extrudate within less than 5 min.

Example 36: 10 kg Batch of Coated Granulate

A premix was prepared my melting 8.25 kg palm stearin (Palm Stearin 54,Bressmer, Germany) in a cooking pot over an induction plate. When themelt had a temperature of 60° C., 4.5 kg sodium alginate (Satialgine®,Cargill, France), 1.5 g oat fibre preparation (PromOat®, Tate & Lyle,Sweden) and 1.5 kg pectin (Pektin HV, Golden Peanut, Germany) wereincorporated by means of a cooking spoon. The mixture was transferred inaliquots into zip-loc plastic bags and cooled to room temperature toform solid plates. Lipid-polymer plates were further cooled in a freezerset at −18° C. and then shredded to particles of ca. 5 mm and smaller bymeans of a blender (Vitamix®, Vita-Mix Corp., USA). The obtained premixwas fed via a volumetric dosing system (Dosimex DO-50, Gabler, Germany)into a powder inlet of a twin screw extruder (Extruder DE-40/10, Gabler,Germany, operating at 10 rpm) and extruded at a temperature range of10-12° C. to strands of 1.5 mm diameter. Extruded strands were cut togranules of 0.8-2.5 mm length by means of rotating blades (running at100 rpm). The premix was quantitatively converted into extrudate withinless than 5 min. The extrudate was transferred into plastic bags inaliquots of 990 g and stored at −18° C. To each bag, 9.9 g of PromOat®powder were added and thoroughly mixed with the extrudate. Subsequently,granules were optionally dried under vacuum at 25° C. and subjected toclassification using a wire mesh sieves of 2 mm (mesh 10) and 1.0 mm(mesh 18). The classified granules were mixed and split into aliquots of600 g. Aliquots were loaded into a fluid bed device (Ventilus V-2.5/1,Innojet, Germany, equipped with an IPC3 product reservoir) and fluidisedat a bed temperature of 20° C. at an air flow of 80 cubic meters/h. 120g Dynasan® 115 were molten in a beaker on a hot plate (at 90° C.)equipped with an overhead stirrer. The hot melt was quantitativelysprayed onto the granulate using a peristaltic pump and a top sprayingprocedure at a spray rate of 6.5 g/min. Aliquots were combined and atotal of 10 kg of coated granulate was obtained and stored in a plasticcontainer.

Example 37: Coated Granulate

Fourteen kg of a premix were prepared in seven batches of 2 kg each. Foreach batch, 0.9 kg palm stearin (Prifex® 300, Unimills, The Netherlands)and 0.1 kg linseed oil (manako BIO Leinöl human, Makana, Germany) werebrought to a melt in a cooking pot over an induction plate. When themelt had a temperature of 60° C., 0.3 kg sodium alginate (Alginex®,Kimica, Japan), 0.1 kg oat fibre preparation (PromOat®, Tate & Lyle,Sweden) and 0.1 kg pectin (Aglupectin® HS-RVP, Silva, Italy) wereincorporated by means of a cooking spoon. The mixture was transferred inaliquots into zip-loc plastic bags and cooled to room temperature toform solid plates. Lipid-polymer plates were further cooled in a freezerset at −18° C. and then shredded to particles of ca. 5 mm and smaller bymeans of a blender (Vitamix® Professional 750, Vita-Mix Corp., USA). Theobtained premix was fed via a volumetric dosing system (Dosimex DO-50Gabler, Germany) into a powder inlet of a twin screw extruder (ExtruderDE-40/10, Gabler, Germany, operating at 10 rpm) and extruded at atemperature range of ca. 30° C. to strands of 1.0 mm diameter. Extrudedstrands were cut to granules of 0.8-2.5 mm length by means of rotatingblades (running at 100 rpm). The extrudate was transferred into plasticbags in aliquots and stored at −18° C. Subsequently, granules wereoptionally dried under vacuum at 25° C. and subjected to classificationusing a wire mesh sieves (Atechnik, Germany) of 2 mm (mesh 10) and 1.0mm (mesh 18). Material retained on the 2 mm sieve was subjected tocomminution using a household blending device (MK55300, Siemens,Germany) and re-classified using the set of wire mesh sieves. Granulesclassified to a range of 1-2 mm were combined to give a yield of 9.0 kgand split into aliquots of 600 g. Batches (one aliquot per run, fifteenruns) were loaded into a fluid bed device

(Ventilus V-2.5/1, Innojet, Germany, equipped with an IPC3 productreservoir) and fluidised at a bed temperature of 20° C. at an air flowof 65 m³/h. Per run, 120 kg palm stearin (Prifex® 300, Unimills, TheNetherlands) were molten in a beaker on a hot plate (at 100° C.)equipped with an overhead stirrer. The hot melt was quantitativelysprayed onto the granulate using a peristaltic pump and a top sprayingprocedure at a spray rate of 6.5 g/min. Batches were combined, and atotal of 10.67 kg of coated granulate was obtained and stored in aplastic container.

Example 38: Preparation of Tryptophan-Containing Granules

Granules was prepared by melting 2 g glycerol monolaurin (Mosselman,Belgium) and 2 g glycerol monoolein 40 (TCI, Belgium) at 55° C.L-Tryptophan (1 g, TCI, Belgium), hydroxypropyl methylcellulose(Metolose® 90SH-100000SR, Harke, Germany), and xanthan gum (0.5 g,Solegraells, Spain) were incorporated by mechanical mixing. Thecomposition was transferred into a zip-loc-bag and cooled to −18° C. ina freezer. The material was first crushed by means of a hammer, shreddedinto a granulate using a kitchen blender (Bosch ProfiMIXX, Germany),optionally dried under vacuum at 25° C. and then classified through aset of wire mesh sieves (VWR International, Germany) to a granule sizeof below 1.0 mm and above 0.5 mm.

A sample of 200 mg of tryptophan-containing granules was suspended in 22mL fasted-state simulated gastric fluid (FaSSGF) at 37° C. and agitated(shaker ST5 from CAT, Germany). FaSSGF was prepared by dissolving 1 g ofNaCl (Sigma-Aldrich) in 450 mL of water, adding 30 mg of SIF powder(biorelvant.com), adjusting the pH to 2.0 with 0.1 N HCl (Sigma-Aldrich)and adding water to a final volume of 500 mL. Aliquots were removed fromthe supernatant at time intervals of 15 min, and the tryptophanconcentration was determined by absorption measurement at a wavelengthof 280 nm in a NanoDrop® 2000 device (Thermo Scientific, USA).Tryptophan release followed first-order kinetics with a half-time of 20minutes.

A sample of 200 mg of tryptophan-containing granules was suspended in 22mL fasted-state simulated intestinal fluid (FaSSIF) at 37° C. andagitated (shaker ST5 from CAT, Germany). FaSSIF was prepared bydissolving 0.21 g NaOH pellets (Sigma-Aldrich), 3.09 g of NaCl(Sigma-Aldrich) and 1.98 g sodium dihydrogen phosphate monohydrate(Sigma-Aldrich) in 450 mL of water, adding 1.12 g of SIF powder(biorelvant.com), adjusting the pH to 6.5 and adding water to a finalvolume of 500 mL. Aliquots were removed from the supernatant at timeintervals of 15 min, and tryptophan concentration was determined byabsorption measurement at a wavelength of 280 nm in a NanoDrop® 2000device (Thermo Scientific, USA). Tryptophan release followed first-orderkinetics with a half-time of 15 minutes.

Tryptophan Control

30 mg of tryptophan powder were suspended in 22 mL FaSSGF at 37° C. andagitated (shaker ST5 from CAT, Germany). Aliquots were removed at timeintervals of 5 min, and tryptophan concentration was quantified usingabsorption measurement at a wavelength of 280 nm in a NanoDrop® 2000device (Thermo Scientific, USA). Tryptophan was quantitatively dissolvedafter 10 minutes.

1. An ingestible particle having a sieve diameter in the range from 0.05to 3 mm, comprising (a) a water-swellable or water-soluble polymericcomponent, and (b) a first lipid component, and optionally (c) an aminoacid, (d) a vitamin, and/or (e) a micro-nutrient; wherein the firstlipid component comprises a medium or long chain fatty acid compound,and the water-swellable or water-soluble polymeric component is embeddedwithin, and/or coated with, the lipid component.
 2. The particle ofclaim 1, comprising an active core and a coating, wherein the activecore comprises the water-swellable or water-soluble polymeric componentand the first lipid component, the coating comprises a second lipidcomponent and/or a hydrophilic component, wherein the coating may besubstantially free of the water-swellable or water-soluble polymericcomponent, and wherein the composition of the second lipid component maybe the same as, or different from, the composition of the first lipidcomponent.
 3. The particle of claim 1, comprising an inert core, a firstcoating covering the inert core, and a second coating covering the firstcoating, wherein the first coating comprises the water-swellable orwater-soluble polymeric component and the first lipid component, andwherein the second coating comprises a second lipid component and/or ahydrophilic component, wherein the second coating is substantially freeof the water-swellable or water-soluble polymeric component, and whereinthe composition of the second lipid component may be the same as, ordifferent from, the composition of the first lipid component.
 4. Theparticle of claim 1, wherein the water-swellable or water-solublepolymeric component comprises at least one polymeric material selectedfrom poly(carboxylate), chitosan, cellulose ethers, and xanthan gum; andwherein the poly(carboxylate) is preferably selected from alginic acid,poly(acrylic acid), poly(methacrylic acid), copolymers of acrylic andmethacrylic acid, poly(hydroxyethyl methacrylic acid); wherein thecellulose ether is preferably selected from hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose,and carboxymethylcellulose; wherein the poly(carboxylate) and/or thecarboxymethylcellulose is optionally partially or entirely neutralised;and wherein the polymeric material is optionally at least partiallycrosslinked.
 5. The particle of claim 1, wherein the water-swellable orwater-soluble polymeric component comprises a plant fibre such aspsyllium seed husk fibre or oat beta glucan, or a carbomer.
 6. Theparticle of claim 1, wherein the amino acid is selected from (a) L-aminoacids; (b) the group consisting of L-isoleucine, L-valine, L-tyrosine,L-methionine, L-lysine, L-arginine, L-cysteine, L-phenylalanine,L-glutamate, L-glutamine, L-leucine, and L-tryptophan; (c) the groupconsisting of L-phenylalanine, L-leucine, L-glutamine, L-glutamate, andL-tryptophan; or (d) L-tryptophan.
 7. The particle of claim 1, whereinthe vitamin is selected from retinol, retinal, beta carotene, thiamine,cyanocobalamine, hydroxycyanocobalamine, methylcobalamine, riboflavin,niacin, niacinamide, pantothenic acid, pyridoxine, pyridoxamine,pyridoxal, biotin, folic acid, folinic acid, ascorbic acid,cholecalciferol, ergocalciferol, tocopherol, tocotrienol, phylloquinone,and menaquinone.
 8. The particle of claim 1, wherein the micro-nutrientis selected from organic acids, such as acetic acid, citric acid, lacticacid, malic acid, choline or taurine; trace minerals such as salts ofboron, cobalt, chromium, calcium, copper, fluoride, iodine, iron,magnesium, manganese, molybdenum, selenium, zinc, sodium, potassium,phosphorus, or chloride; and cholesterol.
 9. The particle of claim 1,wherein (a) the medium or long chain fatty acid compound in the firstlipid component has a melting range below 37° C.; and/or (b) the weightratio of the first lipid component to the water-swellable orwater-soluble polymeric component is in the range from 0.1 to
 10. 10.The particle of claim 1, essentially consisting of the water-swellableor water-soluble polymeric component, the first lipid component, andoptionally the amino acid(s), the vitamin(s), the micro-nutrient(s), thesecond lipid component, and optionally one or more pharmacologicallyinert excipients.
 11. The particle of claim 1, being in the form of agranule, a pellet, or a minitablet.
 12. A method for the preparation ofthe particle according to claim 1, comprising a step of processing amixture comprising the first lipid component and the water-swellable orwater-soluble polymeric component by (a) extruding the mixture using ascrew extruder; (b) spray congealing the mixture, optionally using ajet-break-up technique; (c) melt granulating the mixture; (d)compressing the mixture into minitablets; (e) melt injection of themixture into a liquid medium; (f) spray coating of the mixture ontoinert cores.
 13. An ingestible particle obtainable by the method ofclaim
 12. 14. A solid composition for oral administration comprising aplurality of particles of claim 1, wherein the particles in thecomposition optionally have a mass median sieve diameter in the rangefrom 0.1 mm to 3 mm, and/or wherein the dynamic angle of repose of asuspension prepared from suspending the composition in water at a weightratio of 1 is less than 30°.
 15. A solid composition for oraladministration obtainable by compressing a plurality of particles ofclaim 1 into tablets.
 16. The composition of claim 14, essentiallyconsisting of the particles of claims 1 to 11 and claim 13, andoptionally one or more pharmacologically inert excipients.
 17. A singledose unit or package comprising the composition of claim 14, wherein theamount of the composition is from 3 g to 20 g, and/or wherein the amountof the first lipid component in the composition is at least 2 g.
 18. Thecomposition of claim 14 and/or the single dose unit or package of claim17 for use in (a) the prevention and/or treatment of obesity; (b) theprevention and/or treatment of a disease or condition associated withobesity; (c) appetite suppression; (d) the induction of satiety; and/or(e) body weight reduction; wherein the use optionally comprises the oraladministration of the composition at least once a day over a period ofat least one week.
 19. The composition for use according to claim 18,further comprising the use of a device for the collection, storageand/or display of information relating to a subject's adherence to thetherapy and/or the effectiveness of the therapy, wherein the device isoptionally a wearable device.